Nadph oxidase 4 inhibitors

ABSTRACT

The invention relates to 2,5-disubstituted benzoxazole and benzothiazole derivatives of Formula (I)wherein L, X, Y, and ring (A) are as described in the description, their preparation and their use as pharmaceutically active compounds. Said compounds may be useful for the prevention or treatment of diseases or disorders associated with impaired reactive oxygen species (ROS) production, and/or for the prevention or treatment of various fibrotic diseases.

The present invention relates to NADPH oxidase 4 inhibitors of Formula(I) and their use as active ingredients in the preparation ofpharmaceutical compositions. The invention also concerns related aspectsincluding processes for the preparation of the compounds, pharmaceuticalcompositions containing a compound of the Formula (I), and their use ascompounds treating fibrotic diseases or disorders associated withimpaired reactive oxygen species (ROS) production, either alone or incombination with other active compounds or therapies.

ROS are oxygen-derived small molecules that are formed upon incompletereduction of oxygen and include, besides superoxide anion [.O₂—],hydrogen peroxide [H₂O₂], hydroxyl —[HO.], -alkoxyl —[RO.], peroxyl—[ROO.], and hydroperoxyl radicals [HOO.]. .O₂— can further react withnitric oxide to form peroxynitrite or dismutate, either spontaneously orcatalyzed by superoxide dismutase, to H₂O₂. H₂O₂ is further catalyzed tohypochlorous acid by peroxidase-mediated reaction or to hydroxyl radicalby the iron-catalyzed Fenton reaction.

ROS can interact with nucleic acids, proteins, lipids, carbohydrates,but also with other small inorganic molecules. Depending on their natureROS can modulate a multitude of reversible redox-sensitive signalingpathways, such as those downstream of growth factor receptors. Inaddition to regulating diverse physiological processes ROS can be toxicto cells since ROS can also irreversibly destroy or alter the functionof target molecules and thereby induce oxidative stress.

NADPH oxidases (NOX) are enzymes that transport electrons acrosscell—and organelle membranes. NADPH-derived electrons are firsttransported to a bound flavin adenine nucleotide (FAD), which in turnpasses electrons sequentially to the two heme groups bound to thetransmembrane alpha helices of the NOX proteins and ultimately to oxygento generate .O2-. The biological function of NOX enzymes is thereforethe generation of ROS. Seven members of the NOX family have beenidentified in humans: NOX1, NOX2, NOX3, NOX4, NOX5, as well as the dualNADPH oxidases/peroxidases Duox1 and Duox2 (Bedard, K., Krause, K. H.The NOX family of ROS-generating NADPH oxidases: physiology andpathophysiology. Physiol Rev (2007), 87(1), 245-313)

NOX4 is ubiquitously expressed in non-phagocytic cells with highexpression in the proximal and distal tubules of the kidney. ModerateNOX4 mRNA levels are found in various cell types such as, but notlimited to, endothelial cells, smooth muscle cells, fibroblasts, hepaticstellate cells, hepatocytes, hematopoietic stem cells, osteoclasts,keratinocytes, neurons, astrocytes, microglia and in various cancercells (Babelova, A. et al., Role of NOX4 in murine models of kidneydisease. Free Radic Biol Med (2012) 53(4):842-53; Bedard, K., Krause, K.H. Physiol Rev (2007), 87(1), 245-313).

Induction of NOX4 has been linked to the differentiation of mesenchymalcells such as myofibroblasts, adipocytes, smooth muscle cells andcardiac myocytes (Clempus, R. E., et al. NOX4 is required formaintenance of the differentiated vascular smooth muscle cell phenotype.Arterioscler Thromb Vasc Biol 27, 42-48 (2007); Cucoranu, I., et al.NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induceddifferentiation of cardiac fibroblasts into myofibroblasts. Circ Res 97,900-907 (2005); Li, J., et al. The NADPH oxidase NOX4 drives cardiacdifferentiation: Role in regulating cardiac transcription factors andMAP kinase activation. Mol Biol Cell 17, 3978-3988 (2006); Schroder, K.et al. NOX4 acts as a switch between differentiation and proliferationin preadipocytes. Arterioscler Thromb Vasc Biol 29, 239-245 (2009)).

Increased NOX4 activity has been implicated in a number of pathologiesincluding fibrotic diseases and/or diseases or disorders associated withan impaired reactive oxygen species (ROS) production.

Fibrosis involves the synthesis and deposition of extracellular matrixcomponents such as collagens, fibrillins, proteoglycans and adhesionmolecules. In fibrotic diseases healthy tissue is lost due toreplacement by fibrotic scar tissue. This leads to disruption of tissuearchitecture and, hence, to compromised organ function. A key event inthe onset of fibrotic disease is the differentiation of fibroblast cellsinto extracellular matrix synthesizing myofibroblasts. Thisdifferentiation can be initiated by soluble mediators such as, but notlimited to, transforming growth factor-beta1 (TGF-β1). Thesepro-fibrotic stimuli can trigger resident fibroblasts to produce ROS byeither activating or inducing NOX enzymes. These ROS have been shown toamplify the pro-fibrotic signal that results in the differentiation offibroblasts to myofibroblasts with increased extracellular matrixsynthesis, proliferation and survival of these cells (Cucoranu, I., etal. Circ Res 97, 900-907 (2005)).

Diseases in which fibrosis plays a significant pathogenic role include,but are not limited to, pulmonary fibrosis, scleroderma (systemicsclerosis), pancreatic fibrosis, liver fibrosis, diabetic nephropathy,cardiac fibrosis and heart failure.

NOX4 expression is increased in lungs of and in fibroblasts isolatedfrom IPF patients and in rodents subjected to bleomycin-induced lunginjury (Amara, N. et al., NOX4/NADPH oxidase expression is increased inpulmonary fibroblasts from patients with idiopathic pulmonary fibrosisand mediates TGFβ1-induced fibroblast differentiation intomyofibroblasts. Thorax 65, 733-738 (2010); Hecker, L. et al., NADPHoxidase-4 mediates myofibroblast activation and fibrogenic responses tolung injury. Nat Med 15, 1077-1081 (2009)). Fibroblasts isolated fromlungs of patients with idiopathic pulmonary fibrosis (IPF) generateextracellular H₂O₂ in response to TGF-β and thereby induce loss ofviability and death of co-cultured small airway epithelial cells(Waghray, M. et al., Hydrogen peroxide is a diffusible paracrine signalfor the induction of epithelial cell death by activated myofibroblasts.FASEB J 19, 854-856 (2005)). Genetic or pharmacological targeting ofNOX4 abrogates fibrogenesis in rodent models of lung injury(Carnesecchi, S. et al., A key role for NOX4 in epithelial cell deathduring development of lung fibrosis. Antioxid Redox Signal (2011);Hecker, L. et al., Reversal of persistent fibrosis in aging by targetingNOX4-NRF2 redox imbalance. Sci Transl Med 6, 231-247 (2014); Jarman, E.R. et al., An Inhibitor of NADPH Oxidase-4 Attenuates EstablishedPulmonary Fibrosis in a Rodent Disease Model. Am J Respir Cell Mol Biol,50(1):158-169 (2013)). Thus, NOX4 plays an important role in lungfibrosis and therapeutic targeting of NOX4 can be an effective strategyfor the treatment of fibrotic lung diseases and/or disorders.

Numerous studies have shown increased ROS production by various cells insystemic sclerosis (SSc), as well as elevated ROS levels in plasma fromSSc patients (Piera-Velazquez et al., Role of cellular senescence andNOX4-mediated oxidative stress in systemic sclerosis pathogenesis. CurrRheumatol Rep 17, 473 (2015)). In SSc fibroblasts protein tyrosinephosphatase 1B (PTP1B) activity was significantly reduced whileplatelet-derived growth factor receptor (PDGFR) phosphorylation wasincreased (Tsou, P. S. et al., Effect of oxidative stress on proteintyrosine phosphatase 1B in scleroderma dermal fibroblasts. ArthritisRheum 64, 1978-1989 (2012)). NOX4-mediated oxidation and inactivation ofPTP1B serves as a regulatory switch for intracellular tyrosine kinasesignaling (Chen, K. et al., Regulation of ROS signal transduction byNADPH oxidase 4 localization. J Cell Biol 181, 1129-1139 (2008)). Thus,NOX4-mediated oxidative inactivation of PTP1B leading to pronouncedPDGFR activation may be involved in the pathogenesis of sclerodermaproviding a rationale for treating SSc patients with a pharmacologicalNOX4 inhibitor.

Oxidative stress is implicated in pancreatic fibrosis and activatedpancreatic stellate cells (PSCs) play an important role in this disease.The activation of PSCs is NOX-dependent and thus, NOX enzymes arepotential targets for treatment of pancreatic fibrosis (Masamune, A. etal., NADPH oxidase plays a crucial role in the activation of pancreaticstellate cells. Am J Physiol Gastrointest Liver Physiol 294, G99-G108(2008)).

Liver fibrosis is the result of chronic liver disease and characterizedby activation of hepatic stellate cells (HSCs). NOX4 mediates activationof HSC which are a major source of extracellular matrix components.Hepatic gene expression analysis in patients with alcoholic hepatitisand in patients with hepatitis C virus-derived fibrosis showed stronglyelevated NOX4 (Colmenero, J. et al., Hepatic expression of candidategenes in patients with alcoholic hepatitis: correlation with diseaseseverity. Gastroenterology 132, 687-697 (2007)). Increased NOX4expression was also observed in animal models of liver fibrosis (Sancho,P. et al., NADPH Oxidase NOX4 Mediates Stellate Cell Activation andHepatocyte Cell Death during Liver Fibrosis Development. PLoS One 7(9),e45285 (2012)). Use of a pharmacological NOX1/4 inhibitor effectivelydecreased liver fibrosis in two mouse models (Aoyama, T. et al.,Nicotinamide adenine dinucleotide phosphate oxidase (NOX) inexperimental liver fibrosis: GKT137831 as a novel potential therapeuticagent. Hepatology 56(6):2316-27 (2012)). Targeting NOX4 with apharmacological inhibitor might thus be beneficial in liver diseaseassociated with fibrosis.

Diabetic nephropathy, or chronic kidney disease, is an associatedco-morbidity of diabetes. Diabetic mellitus causes increased ROSformation in the kidney that result in glomerular damage and ultimatelyleads to renal failure. Pharmacological inhibition and genetic deletionof NOX4 effectively improved the outcome in mouse models of diabeticnephropathy (Jha, J. C. et al., Genetic Targeting or PharmacologicInhibition of NADPH Oxidase NOX4 Provides Renoprotection in Long-TermDiabetic Nephropathy. J Am Soc Nephrol 25(6):1237-54 (2014);Thallas-Bonke, V. et al., NOX-4 deletion reduces oxidative stress andinjury by PKC-alpha-associated mechanisms in diabetic nephropathy.Physiol Rep 2 2(11). pii: e12192 (2014)) supporting the use of NOX4inhibitors in diabetic nephropathy.

Diabetic patients have an increased risk of developing cardiomyopathywhich ultimately can lead to heart failure. Hyperglycemia can triggerthe formation of ROS resulting in myocardial collagen deposition andfibrosis. NOX4-derived ROS of left ventricular origin have been shown tocontribute to cardiomyopathy in a rat model for type 1 diabetes(Maalouf, R. M. et al., NOX4-Derived Reactive Oxygen Species MediateCardiomyocyte Injury In Early Type 1 Diabetes. Am J Physiol Cell Physiol302(3):C597-604 (2011)). Prevention of oxidative stress by means ofinhibition of NOX4 could thus provide a therapeutic benefit fortreatment of diabetic cardiomyopathy.

ROS are increased in the hypertrophic heart and in heart failurepatients and the expression of NOX4 is increased in response tohypertrophic stimuli and aging (Ago, T. et al., Upregulation of NOX4 byhypertrophic stimuli promotes apoptosis and mitochondrial dysfunction incardiac myocytes. Circ Res 106, 1253-1264 (2010)). Upregulation of NOX4in the myocardium causes remodeling of the heart with increased cardiacfibrosis and hypertrophy (Zhao, Q. D. et al., NADPH Oxidase 4 InducesCardiac Fibrosis and Hypertrophy Through Activating Akt/mTOR andNFkappaB Signaling Pathways. Circulation 131(7):643-55 (2015)). Inresponse to pressure overload caused by transverse aortic constriction,mice with cardiac-specific deletion of NOX4 gene showed blunted ROSproduction, attenuated cardiac hypertrophy, better cardiac function andless fibrosis compared with wild-type mice (Kuroda, J. et al., NADPHoxidase 4 (NOX4) is a major source of oxidative stress in the failingheart. Proc Natl Acad Sci USA 107, 15565-15570 (2010)). This supportsthe idea that treatment of patients suffering from cardiac hypertrophyand cardiac fibrosis progressing towards heart failure might benefitfrom interventions targeting NOX4.

Impaired reactive oxygen species (ROS) production may be linked tohypertension, asthma, acute respiratory distress syndrome (ARDS),myocardial infarction and heart failure, myopathies such as Barthsyndrome, stroke, traumatic brain injury, neuropathic pain, ataxiatelangiectasia, ocular diseases, such as diabetic renopathy, and variousforms of cancer.

In lungs from patients with idiopathic pulmonary arterial hypertension(IPAH), NOX4 transcript levels were increased (Mittal, M. et al.,Hypoxia-dependent regulation of nonphagocytic NADPH oxidase subunit NOX4in the pulmonary vasculature. Circ Res 101, 258-267 (2007)). NOX4expression is increased in animal models of PH (Barman, S. A. et al.,NADPH Oxidase 4 Is Expressed in Pulmonary Artery Adventitia andContributes to Hypertensive Vascular Remodeling. Arterioscler ThrombVasc Biol 34(8):1704-15 (2014)) and pharmacological inhibition of NOX4attenuates hypoxia-induced vascular remodeling in a mouse model for PH(Green, D. E. et al., The NOX4 Inhibitor, GKT137831, AttenuatesHypoxia-Induced Pulmonary Vascular Cell Proliferation. Am J Respir CellMol Biol 47(5):718-26 (2012)). These results support an important rolefor NOX4 in the vascular remodeling associated with development ofpulmonary hypertension.

Infiltration of eosinophils into the lung is one of the hallmarks ofasthma. NOX-derived ROS in the endothelium are necessary for eosinophilrecruitment during allergic airway inflammation (Abdala-Valencia, H. etal., Nonhematopoietic NADPH oxidase regulation of lung eosinophilia andairway hyperresponsiveness in experimentally induced asthma. Am JPhysiol Lung Cell Mol Physiol 292, L1111-1125 (2007)). Asthma isconsidered an airway obstruction that can be reversed bybronchodilators, but in a number of patients, the condition ischaracterized by progressive airway remodeling. A pathological featureof this process is enlargement of the bronchial smooth muscle mass,which increases with progression from moderate to severe asthma. NOX4was shown to promote TGF-β1-induced proliferation and hypertrophy ofhuman airway smooth muscle cells. Therefore, TGF-β1- and NOX4-mediatedsignaling may play a pivotal pathogenic role in the development ofbronchial smooth muscle remodeling in asthma (Sturrock, A. et al., NOX4mediates TGF-β1-induced retinoblastoma protein phosphorylation,proliferation, and hypertrophy in human airway smooth muscle cells. Am JPhysiol Lung Cell Mol Physiol 292, L1543-1555 (2007)).

The acute respiratory distress syndrome (ARDS) is a disease with highmortality, no drug therapy, and poorly understood pathogenesis. Thehallmark of ARDS is persistent pulmonary edema. TGF-β levels have beenfound elevated in lavage fluids of patients with ARDS and TGF-β has beenshown to promote lung fluid imbalance in a Bleomycin-induced lung injurymodel for ADRS. TGF-β effects on lung fluid accumulation has been linkedto ROS generated by NOX4 and mice with a genetic deletion of the NOX4gene were fully protected in this animal model. Thus, NOX4 activitymight be targeted in an attempt to normalize alveolar fluid clearance inaffected patients (Peters, D. M. et al., TGF-β directs trafficking ofthe epithelial sodium channel ENaC which has implications for ion andfluid transport in acute lung injury. Proc Natl Acad Sci USA111(3):E374-83 (2013)).

NOX4 acts as an oxygen sensor and induction of NOX4 in ischemia has beenassociated with various diseases and/or disorders. Morbidity andmortality associated with acute myocardial infarction (MI) and heartfailure are associated with uncontrolled neurohormonal excitation thatcan lead to cardiovascular deterioration. ROS generated in theparaventricular nucleus (PVN) are causally linked to sympatheticoveractivity and declining cardiac function after MI. NOX4 has beenidentified as the primary source of ROS in the PVN after MI (Infanger,D. W. et al., Silencing NOX4 in the paraventricular nucleus improvesmyocardial infarction-induced cardiac dysfunction by attenuatingsympathoexcitation and periinfarct apoptosis. Circ Res 106, 1763-1774(2010)). Antioxidant therapies targeted to the hypothalamus may providea novel strategy for the treatment of MI-induced heart failure.

Barth syndrome (BTHS) is a genetic cardiac and skeletal mitochondrialmyopathy. Using induced pluripotent stem cell-derived cardiomyocytes(iPSC-CMs) it has been shown that ROS production was markedly enhancedin these cells. Suppression of excessive ROS in BTHS iPSC-CMs normalizedsarcomere organization and contractility of these cells, indicating thatprevention of excessive ROS generation might be a target for futuretherapeutic intervention in myopathies, more specifically in BTHS (Wang,G. et al., Modeling the mitochondrial cardiomyopathy of Barth syndromewith induced pluripotent stem cell and heart-on-chip technologies. NatMed 20, 616-623 (2014)).

Excessive ROS are suspected to cause tissue damage and neuronal deathpost stroke. In a model of acute ischemic stroke in which mice aresubjected to transient middle cerebral artery occlusion NOX4 has beenidentified to be a key contributor and a major source of oxidativestress. Deletion of the NOX4-coding gene in mice, as well as inhibitingthe ROS-generating activity of NOX with a small molecule inhibitor,reduced brain damage and improved neurological function (Kleinschnitz,C. et al., Post-stroke inhibition of induced NADPH oxidase type 4prevents oxidative stress and neurodegeneration. PLoS Biol 8(9). pii:e1000479 (2010)). Therefore, NOX4 inhibition is considered a potentialtreatment for acute stroke.

NOX4 was found to be expressed in neurons, astrocytes, and microglia,and its expression was increased under ischemic conditions. NOX4, maythus contribute to oxidative stress observed acutely after traumaticbrain injury and future therapeutic approaches might include NOX4inhibitors (Cooney, S. J. et al., Cellular and temporal expression ofNADPH oxidase (NOX) isotypes after brain injury. J Neuroinflammation 10,155 (2013); Vallet, P. et al., Neuronal expression of the NADPH oxidaseNOX4, and its regulation in mouse experimental brain ischemia.Neuroscience 132, 233-238 (2005)).

In neuropathic pain after nerve injury NOX4-derived ROS essentiallycontribute to the processing of peripheral nerve dysmyelination and painhypersensitivity (Im, Y. B. et al., Molecular targeting of NOX4 forneuropathic pain after traumatic injury of the spinal cord. Cell DeathDis 3:e426. (2012); Kallenborn-Gerhardt, W. et al., NADPH oxidase-4maintains neuropathic pain after peripheral nerve injury. J Neurosci 32,10136-10145 (2012); Kallenborn-Gerhardt, W. et al., NOXious signaling inpain processing. Pharmacol Ther 137, 309-317 (2013)). WO 2013/037499 A1discloses the use of inhibitors of NOX4 in the prevention and/ortreatment of nerve injury, in particular pain, more particularlyneuropathic pain.

Ataxia telangiectasia is a rare, autosomal recessive disordercharacterized by progressive cerebellar degeneration. Oxidative stressis one cause of the symptoms of the disease. Elevated levels of NOX4were found in the cerebellum and in cells derived of Ataxia patients.Inhibition of NOX4 by using genetic and/or pharmacological compoundsreduced some of the effects in cellular and in a mouse model for thedisease, respectively (Weyemi, U. et al., NADPH oxidase 4 is a criticalmediator in Ataxia telangiectasia disease. Proc Natl Acad Sci USA112(7):2121-6 (2015)).

Bone formation is ongoing even in adulthood and is mediated byosteoblasts, while osteoclast cells absorb bone. NOX4 is upregulatedduring the differentiation and development of osteoclasts andNOX4-derived ROS can modulate signal transduction pathways necessary forosteoclast function (Yang, S. et al., Expression of NOX4 in osteoclasts.J Cell Biochem 92, 238-248 (2004)). WO 2013/068972 discloses that NOX4controls bone mass by regulation of osteoclastogenesis. Furthermore,evidence is disclosed showing that NOX4 inhibition is beneficial in thetreatment and prevention of osteoporosis and/or an osteoclastogenesisdysfunction.

Oxidative stress plays an important role in vascular endothelialdysfunction in diabetes and diabetic retinopathy is a commoncomplication and one of the most frequent causes of blindness in theU.S. Hallmark sequential pathological changes in diabetic retinopathyinclude increased vascular permeability, pericyte and endothelial celldeath, capillary occlusion and aberrant retinal new vessel growth, orneovascularization. In primary bovine retinal capillary endothelialcells (RCECs) Nox4 expression is significantly higher than Nox2 andNox1. Exposure of RCECs to hypoxia upregulates Nox4 mRNA and proteinexpression. In human retinal microvascular endothelial cells (HRECs),overexpression of Nox4 by adenovirus significantly increasedextracellular H₂O₂ generation, resulting in intensified VEGFR2activation and exacerbated angiogenesis upon VEGF stimulation (Li, J. etal., Inhibition of reactive oxygen species by Lovastatin downregulatesvascular endothelial growth factor expression and amelioratesblood-retinal barrier breakdown in db/db mice: role of NADPH oxidase 4.Diabetes. June; 59(6):1528-38 (2010); Li, J. et al., NADPH oxidase4-derived H₂O₂ promotes aberrante retinal neo-vascularization viaactivation of VEGF receptor 2 pathway in oxygen-induced retinopathy. JDiabetes Res. 2015:963289 (2015))

NOX4 has been identified as a potential target for cancer. Studies havepostulated a role for NOX4 in ischemia/hypoxia-induced angiogenesis(Craige, S. M. et al., NADPH Oxidase 4 Promotes Endothelial AngiogenesisThrough Endothelial Nitric Oxide Synthase Activation. Circulation124(6):731-40 (2011)). Angiogenesis is important for tumor developmentand growth. The hypoxic tissue responds with HIF-1α activation andvascular endothelial growth factor (VEGF) production, which leads toVEGF-induced neovascularization response of the endothelial cells.Ovarian cancer cells showed elevated ROS production and NOX4 knockdownin ovarian cancer cells decreased the levels of VEGF and HIF-1α andtumor angiogenesis (Xia, C. et al., Reactive oxygen species regulateangiogenesis and tumor growth through vascular endothelial growthfactor. Cancer Res 67, 10823-10830 (2007)).

Inactivation of the von Hippel-Lindau tumor suppressor (VHL) occursearly in the disease progression of renal cell carcinoma (RCC). Loss ofVHL function results in accumulation of the alpha-subunit of thehypoxia-inducible transcription factor (HIF-α). Increased HIF-1a andHIF-2α contribute to the pathogenesis of RCC. Renal NOX4 expression isessential for full HIF-2α expression and activity in renal tumor cells,even in the absence of functional VHL (Maranchie, J. K., Zhan, Y. NOX4is critical for hypoxia-inducible factor 2-alpha transcriptionalactivity in von Hippel-Lindau-deficient renal cell carcinoma. Cancer Res65, 9190-9193 (2005)). NOX4 has been shown to mediate RCC cell invasionthough a hypoxia-mediated pathway (Fitzgerald, J. P. et al., NOX4mediates renal cell carcinoma cell invasion through hypoxia-inducedinterleukin 6- and 8-production. PLoS One 7(1):e30712 (2012)) and tocontribute to RCC chemo-resistance through modulation of pro-apoptoticsignaling. This suggests that NOX4 inhibition might be a target in thetreatment of RCC and enhance the efficacy of cytotoxic drugs against RCC(Chang, G. et al., NOX4 inhibition enhances the cytotoxicity ofcisplatin in human renal cancer cells. J Exp Ther Oncol 10, 9-18(2012)).

NOX4-generated ROS were required for hypoxia-induced tumor cell invasionand infiltration in glioblastoma (Hsieh, C. H. et al., NADPH oxidasesubunit 4-mediated reactive oxygen species contribute to cyclinghypoxia-promoted tumor progression in glioblastoma multiforme. PLoS One6(9):e23945 (2011); Hsieh, C. H. et al., Imaging the Impact of NOX4 inCycling Hypoxia-mediated U87 Glioblastoma Invasion and Infiltration. MolImaging Biol 14, 489-499 (2012); Shono, T. et al., Enhanced expressionof NADPH oxidase NOX4 in human gliomas and its roles in cellproliferation and survival. Int J Cancer 123, 787-792 (2008)).

EGFR inhibitors are routinely used in the treatment of head and necksquamous cell carcinoma (HNSCC). However, many HNSCC tumors becomerefractory to EGFR inhibitors. Activation of autophagy via NOX4-mediatedoxidative stress has been identified to reduce the efficacy ofchemotherapy in HNSCC cells (Sobhakumari, A. et al., NOX4 mediatescytoprotective autophagy induced by the EGFR inhibitor erlotinib in headand neck cancer cells. Toxicol Appl Pharmacol 272, 736-745 (2013)).Therapies targeted to NOX4 may provide a strategy for the treatment ofHNSCC either alone or in combination with EGFR inhibitors.

In pancreatic adenocarcinoma epithelial-mesenchymal transition (EMT) isa prerequisite for tumor invasiveness and metastasis and overexpressionof TGF-β is associated with poor prognosis. NOX4 and TGF-β areup-regulated in tumors from pancreatic cancer patients and NOX4-derivedROS have been identified to transmit TGF-β-triggered EMT signals inpancreatic cancer (Hiraga, R. et al., NOX4-derived ROS signalingcontributes to TGF-β-induced epithelial-mesenchymal transition inpancreatic cancer cells. Anticancer Res 33, 4431-4438 (2013)).

Furthermore, NOX4 is deregulated in various cancers and involved incancer proliferation and metastasis and NOX4 has been identified to behighly predictive of relapse in colon cancer (Bauer, K. M. et al.,Proteomic and functional investigation of the colon cancerrelapse-associated genes NOX4 and ITGA3. J Proteome Res 13, 4910-4918(2014)).

NOX4 was overexpressed in several urothelial carcinoma cell lines andsilencing of NOX4 by siRNA significantly reduced cancer cell growth inan orthotopic mouse model. The data indicate that ROS generation throughNOX4 contributes to an early step of urothelial carcinogenesis andcancer cell survival (Shimada, K. et al., ROS generation via NOX4 andits utility in the cytological diagnosis of urothelial carcinoma of theurinary bladder. BMC Urol 11, 22 (2011)). NOX4 may also play a role instromal remodeling of prostate carcinomas (Sampson, N. et al., ROSsignaling by NOX4 drives fibroblast-to-myofibroblast differentiation inthe diseased prostatic stroma. Mol Endocrinol 25, 503-515 (2011)).

Increased NOX4 was found in breast cancer cell lines as well as inpatient tumor samples and NOX4-dependent ROS may be critical forprogression of the EMT in breast epithelial cells (Boudreau, H. E. etal., NOX4 involvement in TGF-β and SMAD3-driven induction of theepithelial-to-mesenchymal transition and migration of breast epithelialcells. Free Radic Biol Med 53(7):1489-99 (2012)). NOX4 has been shown topromote malignant progression of non-small cell lung cancer (Li, J. etal., Reciprocal activation between IL-6/STAT3 and NOX4/Akt signalingspromotes proliferation and survival of non-small cell lung cancer cells.Oncotarget 6, 1031-1048 (2015); Zhang, C. et al., NOX4 promotesnon-small cell lung cancer cell proliferation and metastasis throughpositive feedback regulation of PI3K/Akt signaling. Oncotarget 5,4392-4405 (2014)) and inhibitors of NOX4 and NOX2 blocked hemangiomagrowth in an experimental model of human endothelial cell-derivedneoplasms (Bhandarkar, S. S. et al., Fulvene-5 potently inhibits NADPHoxidase 4 and blocks the growth of endothelial tumors in mice. J ClinInvest 119, 2359-2365 (2009)).

Thus, NOX4-derived ROS contribute to various types of cancer andcompounds of the present intervention have the potential, either aloneor in combination with existing therapy, to show a benefit in thetreatment of cancer associated with impaired ROS formation.

More general, ROS originating from NOX4 contribute to the pathogenesisof numerous diseases and/or disorders such as, but not limited to,fibrotic diseases, cardiovascular diseases or disorders, respiratorydiseases, pain, bone disorders and cancer. One approach to the treatmentof those diseases associated with ROS overproduction by NOX4 is tosearch for compounds that inhibit NOX4.

Benzoxazole compounds which are inhibitors of Interleukin-6 are knownfrom WO2011/159124. Benzazole compounds as Aurora kinase inhibitors areknown from WO2007/095124. Benzoxazole compounds which are MCH receptorantagonists are known from WO2006/066173. Benzoxazole and benzothiazolecompounds which are H3 receptor ligands are known from WO2009/085945 andWO2007/110364. Certain 2-aminobenzoxazoles are claimed as combinatoriallibrary compounds in WO2002/079753. Certain benzothiazolecarboxamidesare described as tyrosine kinase inhibitors in WO1999/024035.Heterocyclic sulfonamide derivatives which are platelet ADP receptorinhibitors are disclosed in WO2001/085722. Some benzothiazol-6-ylcarboxamide compounds are know as commercial library compounds: CAS930729-55-8, CAS 878583-27-8, CAS 1031064-59-1, CAS 1105223-22-0, CAS1105223-42-4, CAS 1119368-60-3.

The present invention provides novel 2,5-disubstituted benzoxazole andbenzothiazole compounds of Formula (I) that are inhibitors of NADPHoxidase 4 (NOX4). The compounds of the present invention may be useful,alone or in combination with existing drugs, for the prevention ortreatment of diseases or disorders associated with impaired ROSproduction, and/or for the prevention or treatment of various fibroticdiseases.

1) A first embodiment of the invention relates to compounds of theFormula (I):

whereinring (A) represents a non-aromatic 5- to 7-membered heterocyclic ringwhich is fused to the phenyl group; wherein said 5- to 7-memberedheterocyclic ring contains one oxygen ring atom (at the indicatedposition, i.e. in para position to the point of attachment of L) andoptionally one further ring heteroatom independently selected fromoxygen or nitrogen; wherein said 5- to 7-membered heterocyclic ringindependently is unsubstituted, or mono-, or di-substituted, wherein thesubstituents are independently selected from:

-   -   one oxo substituent attached to a ring carbon atom in alpha        position to a ring oxygen and/or a ring nitrogen atom (thus        forming together with a ring nitrogen an amide group; or,        together with a ring oxygen an ester group; or, in case both a        ring oxygen and a ring nitrogen atom are adjacent, a carbamate        group); and/or    -   one C₁₋₃-alkyl (especially methyl) attached to a ring nitrogen        atom having a free valency; or    -   two fluoro substituents attached to the same ring carbon atom;        L represents —NH—CO—* or —CO—NH—*, wherein the asterisks (*)        indicate the bond that is linked to the benzoxazole/the        benzothiazole moiety;        X represents O or S; and        Y represents    -   —NR¹R² wherein        -   —R¹ represents            -   —C₁₋₄-alkyl (especially methyl, ethyl);            -   C₂₋₄-alkyl which is mono-substituted with                di-(C₁₋₃-alkyl)amino, hydroxy or C₁₋₃-alkoxy;            -   C₃₋₅-cycloalkyl-L¹-, wherein L¹ represents a direct bond                or C₁₋₃-alkylene (especially methylene); and wherein the                C₃₋₅-cycloalkyl optionally contains one oxygen ring                atom, and wherein said C₃₋₅-cycloalkyl is unsubstituted,                or mono-substituted with methyl or fluoro (especially                such group C₃₋₅-cycloalkyl-L¹- is oxetan-3-yl,                oxetan-3-yl-methyl, 3-methyl-oxetan-3-yl,                (3-fluoro-oxetan-3-yl)-methyl); or            -   a piperidin-3-yl, piperidin-4-yl or pyrrolidin-3-yl                group, which groups are substituted on the ring nitrogen                atom with C₃₋₅-cycloalkyl, wherein said C₃₋₅-cycloalkyl                optionally contains one oxygen ring atom (especially                such group is 1-(oxetan-3-yl)-piperidin-4-yl); and        -   R² represents hydrogen, C₁₋₃-alkyl (especially methyl,            ethyl), or C₃₋₅-cycloalkyl (especially cyclopropyl);    -   or Y represents a saturated 4- to 7-membered monocyclic        heterocyclyl selected from:        -   morpholin-4-yl; 2-oxo-pyrrolidin-1-yl;            1,1-dioxidothiomorpholin-4-yl; or piperazin-1-yl optionally            mono-substituted in position 4 with oxetan-3-yl or            C₁₋₃-alkyl (especially methyl);        -   or azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl;            wherein said azetidin-1-yl, pyrrolidin-1-yl, or            piperidin-1-yl independently is unsubstituted, or            substituted with:            -   two fluoro substituents attached to the same ring carbon                atom; or            -   one substituent selected from unsubstituted phenyl, or                unsubstituted 5- or 6-membered heteroaryl (especially                pyridinyl); or            -   one substituent selected from hydroxy; C₁₋₃-alkoxy                (especially methoxy, isopropoxy); —CO—C₁₋₄-alkoxy                (especially tert.-butyl-oxy-carbonyl);                di-(C₁₋₃-alkyl)amino (especially dimethylamino); and                C₁₋₃-alkyl which is mono-substituted with                di-(C₁₋₃-alkyl)amino, hydroxy, or C₁₋₃-alkoxy                (especially dimethylamino-methyl,                1-hydroxy-1-methyl-ethyl, ethoxy-methyl); or            -   two substituents, wherein one of said substituents is                C₁₋₄-alkyl (especially methyl), and the other is                independently selected from hydroxy, or                di-(C₁₋₃-alkyl)amino (especially dimethylamino) (wherein                especially said two substituents are attached to the                same ring carbon atom of said heterocyclic group); or            -   one substituent selected from morpholin-4-yl;                1,1-dioxidothiomorpholin-4-yl; or piperazin-1-yl which                is optionally mono-substituted in position 4 with                C₁₋₃-alkyl (especially methyl);            -   one substituent selected from azetidin-1-yl,                pyrrolidin-1-yl, or piperidin-1-yl; wherein said groups                independently are unsubstituted, or mono-substituted                with hydroxy, or di-substituted with methyl and hydroxy                (wherein especially both substituents are attached to                the same ring carbon atom of said group);    -   or Y represents saturated 7- to 11-membered fused, bridged, or        spiro-bicyclic heterocyclyl (especially a 7- to 10-membered        spiro-bicyclic heterocyclyl) containing at least one nitrogen        atom, wherein said nitrogen atom is bound to the benzoxazole/the        benzothiazole moiety, and wherein said heterocyclyl optionally        contains (especially, in the case that such heterocyclyl is a        spiro-bicyclic heterocyclyl, in the distant ring of said        spiro-bicyclic heterocyclyl) one further ring heteroatom        independently selected from oxygen, nitrogen and sulfur; wherein        said heterocyclyl is unsubstituted, or substituted with:        -   two oxo substituents at a ring sulfur ring atom (thus            forming a —SO₂— group); or        -   one C₁₋₃-alkyl substituent (especially methyl) attached to a            ring nitrogen atom having a free valency.

The compounds of formula (I) may contain one or more stereogenic orasymmetric centers, such as one or more asymmetric carbon atoms. Thecompounds of formula (I) may thus be present as mixtures ofstereoisomers or preferably as pure stereoisomers. Mixtures ofstereoisomers may be separated in a manner known to a person skilled inthe art.

The term “enriched”, for example when used in the context of enantiomersis understood in the context of the present invention to mean especiallythat the respective enantiomer is present in a ratio (mutatis mutandis:purity) of at least 70:30, and notably of at least 90:10 (mutatismutandis: purity of 70%/90%) with respect to the respective otherenantiomer. Preferably the term refers to the respective essentiallypure enantiomer. The term “essentially”, for example when used in a termsuch as “essentially pure” is understood in the context of the presentinvention to mean especially that the respectivestereoisomer/composition/compound etc. consists in an amount of at least90, especially of at least 95, and notably of at least 99 percent byweight of the respective pure stereoisomer/composition/compound etc.

Any reference to a compound of Formula (I) is to be understood asreferring also to the salts (and especially the pharmaceuticallyacceptable salts) of such compounds, as appropriate and expedient.

The term “pharmaceutically acceptable salts” refers to salts that retainthe desired biological activity of the subject compound and exhibitminimal undesired toxicological effects. Such salts include inorganic ororganic acid and/or base addition salts depending on the presence ofbasic and/or acidic groups in the subject compound. For reference seefor example “Handbook of Pharmaceutical Salts. Properties, Selection andUse.”, P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008;and “Pharmaceutical Salts and Co-crystals”, Johan Wouters and Luc Quéré(Eds.), RSC Publishing, 2012.

In some instances, the compounds of formula (I) may contain tautomericforms. Such tautomeric forms are encompassed in the scope of the presentinvention.

The present invention also includes isotopically labelled, especially ²H(deuterium) labelled compounds of formula (I), which compounds areidentical to the compounds of formula (I) except that one or more atomshave each been replaced by an atom having the same atomic number but anatomic mass different from the atomic mass usually found in nature.Isotopically labelled, especially ²H (deuterium) labelled compounds offormula (I) and salts thereof are within the scope of the presentinvention. Substitution of hydrogen with the heavier isotope ²H(deuterium) may lead to greater metabolic stability, resulting e.g. inincreased in-vivo half-life or reduced dosage requirements, or may leadto reduced inhibition of cytochrome P450 enzymes, resulting e.g. in animproved safety profile. In one embodiment of the invention, thecompounds of formula (I) are not isotopically labelled, or they arelabelled only with one or more deuterium atoms. In a sub-embodiment, thecompounds of formula (I) are not isotopically labelled at all.Isotopically labelled compounds of formula (I) may be prepared inanalogy to the methods described hereinafter, but using the appropriateisotopic variation of suitable reagents or starting materials.

In case one or more substituent(s) are referred to as being optional,such substituent(s) may be absent (i.e. the parent group isunsubstituted and all positions of the parent group having a freevalency are substituted with hydrogen), or the parent group issubstituted with one or more of such substituent(s), wherein saidsubstituent(s) is/are as explicitly defined.

Where the plural form is used for compounds, salts, pharmaceuticalcompositions, diseases or the like, this is intended to mean also asingle compound, salt, disease or the like.

In this patent application, a bond drawn as a dotted line shows thepoint of attachment of the radical drawn. For example, the radical drawnbelow

is the benzo[d][1,3]dioxol-5-yl group.

Definitions provided herein are intended to apply uniformly to thecompounds of formula (I), as defined in any one of embodiments 1) to16), and, mutatis mutandis, throughout the description and the claimsunless an otherwise expressly set out definition provides a broader ornarrower definition. It is well understood that a definition orpreferred definition of a term defines and may replace the respectiveterm independently of (and in combination with) any definition orpreferred definition of any or all other terms as defined herein.

The term “halogen” means fluorine, chlorine, bromine, or iodine;preferably fluorine or chlorine.

The term “alkyl”, used alone or in combination, refers to a saturatedstraight or branched chain hydrocarbon group containing one to sixcarbon atoms. The term “C_(x-y)-alkyl” (x and y each being an integer),refers to an alkyl group as defined before, containing x to y carbonatoms. For example a C₁₋₄-alkyl group contains from one to four carbonatoms. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl,butyl, isobutyl, and tert.-butyl. For avoidance of any doubt, in case agroup is referred to as e.g. propyl or butyl, it is meant to ben-propyl, respectively n-butyl. Preferred are methyl and ethyl. Mostpreferred is methyl.

Examples of “C₁₋₃-alkyl groups which are mono-substituted withdi-(C₁₋₃-alkyl)amino, hydroxy, or C₁₋₃-alkoxy” are dimethylamino-methyl,1-hydroxy-1-methyl-ethyl, and ethoxy-methyl.

The term “—C_(x-y)-alkylene-”, used alone or in combination, refers tobivalently bound alkyl group as defined before containing x to y carbonatoms. Preferably, the points of attachment of a —C_(1-y)-alkylene groupare in 1,1-diyl, in 1,2-diyl, or in 1,3-diyl arrangement. Preferably,the points of attachment of a —C_(2-y)-alkylene group are in 1,2-diyl orin 1,3-diyl arrangement. For the linker L¹, an example of a—C₁₋₃-alkylene-group is methylene.

The term “alkoxy”, used alone or in combination, refers to an alkyl-O—group wherein the alkyl group is as defined before. The term“C_(x-y)-alkoxy” (x and y each being an integer) refers to an alkoxygroup as defined before containing x to y carbon atoms. For example aC₁₋₄-alkoxy group means a group of the formula C₁₋₄-alkyl-O— in whichthe term “C₁₋₄-alkyl” has the previously given significance. Examples ofalkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec.-butoxy and tert.-butoxy. Preferred are ethoxy andespecially methoxy.

The term “fluoroalkyl”, used alone or in combination, refers to an alkylgroup as defined before containing one to three carbon atoms in whichone or more (and possibly all) hydrogen atoms have been replaced withfluorine. The term “C_(x-y)-fluoroalkyl” (x and y each being an integer)refers to a fluoroalkyl group as defined before containing x to y carbonatoms. For example a C₁₋₃-fluoroalkyl group contains from one to threecarbon atoms in which one to seven hydrogen atoms have been replacedwith fluorine. Representative examples of fluoroalkyl groups includetrifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl and2,2,2-trifluoroethyl. Preferred are C₁-fluoroalkyl groups such astrifluoromethyl.

The term “fluoroalkoxy”, used alone or in combination, refers to analkoxy group as defined before containing one to three carbon atoms inwhich one or more (and possibly all) hydrogen atoms have been replacedwith fluorine. The term “C_(x-y)-fluoroalkoxy” (x and y each being aninteger) refers to a fluoroalkoxy group as defined before containing xto y carbon atoms. For example a C₁₋₃-fluoroalkoxy group contains fromone to three carbon atoms in which one to seven hydrogen atoms have beenreplaced with fluorine. Representative examples of fluoroalkoxy groupsinclude trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy,2,2-difluoroethoxy and 2,2,2-trifluoroethoxy. Preferred areC₁-fluoroalkoxy groups such as trifluoromethoxy and difluoromethoxy.

The term “cyano” refers to a group —CN.

The term “cycloalkyl”, used alone or in combination, refers to asaturated monocyclic hydrocarbon ring containing three to six carbonatoms. The term “C_(x-y)-cycloalkyl” (x and y each being an integer),refers to a cycloalkyl group as defined before containing x to y carbonatoms. For example a C₃₋₆-cycloalkyl group contains from three to sixcarbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and cycloheptyl. Preferred are cyclopropyl,cyclopentyl and cyclohexyl; especially cyclopropyl.

The term “cycloalkyl optionally containing one ring oxygen atom”, usedalone or in combination, refers to a cycloalkyl group as defined before.In addition, one ring carbon atom of said cycloalkyl may be replaced byan oxygen atom. Examples of such groups are cycloalkyl groups such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl; aswell as oxygen containing groups such as oxetanyl, tetrahydrofuranyl,and tetrahydro-2H-pyranyl. When used for example for the substituent R¹(i.e. said cycloalkyl optionally containing one ring oxygen atom isattached to a nitrogen atom) a ring oxygen atom, if present, ispreferably separated from said nitrogen atom by at least two ring carbonatoms. Particular examples of such groups are especially cycloalkylgroups such as cyclopropyl, and cyclobutyl; as well as oxetan-3-yl, andtetrahydrofuran-3-yl. Preferred is oxetan-3-yl. Examples ofmono-substituted cycloalkyl optionally containing one ring oxygen atomas used for the group R¹ are 3-methyl-oxetan-3-yl, 3-fluoro-oxetan-3-yl.

The term “saturated 4- to 7-membered monocyclic heterocyclyl”, usedalone or in combination, and if not explicitly defined in a more narrowway, refers to a saturated hydrocarbon ring containing at least onenitrogen atom, wherein said nitrogen atom is bound to thebenzoxazole/the benzothiazole moiety, and optionally one further ringheteroatom independently selected from oxygen, nitrogen and sulfur. Such“saturated 4- to 7-membered monocyclic heterocyclyl” is unsubstituted,or substituted as explicitly defined.

Examples of “saturated 4- to 7-membered monocyclic heterocyclyl” groupsas used for the substituent Y are:

The term “saturated 7- to 11-membered fused, bridged, or spiro-bicyclicheterocyclyl”, used alone or in combination, and if not explicitlydefined in a more narrow way, refers to a saturated hydrocarbon ringcontaining at least one nitrogen atom, wherein said nitrogen atom isbound to the benzoxazole/the benzothiazole moiety, and optionally onefurther ring heteroatom independently selected from oxygen, nitrogen andsulfur. In the case that such “saturated 7- to 11-membered fused,bridged, or spiro-bicyclic heterocyclyl” is a spiro-bicyclicheterocyclyl, optional further ring heteroatom is preferably a ring atomof the distant ring of said spiro-bicyclic heterocyclyl (i.e. the ringwhich is not bound to the benzoxazole/the benzothiazole moiety). Such“saturated 7- to 11-membered fused, bridged, or spiro-bicyclicheterocyclyl” is unsubstituted, or substituted as explicitly defined.

Examples of “saturated 7- to 11-membered fused, bridged, orspiro-bicyclic heterocyclyl” groups as used for the substituent Y are:

The term “non-aromatic 5- to 7-membered heterocyclic ring which is fusedto the phenyl group” as used for ring (A) refers to a saturated 5- to7-membered heterocyclic ring containing the —C═C— fragment of the phenylring to which it is fused, containing one oxygen ring atom at theindicated position, i.e. in para position to the point of attachment ofL, and optionally containing one further ring heteroatom independentlyselected from oxygen or nitrogen. Such 5- to 7-membered ring isunsubstituted or substituted as explicitly defined. In particular, theterm refers to a bivalent fragment selected from *—O—CH₂—O—,*—O—CH₂—CH₂—O—, *—O—CH₂—CH₂—,*—O—CH₂—CH₂—CH₂—, *—O—CH₂—NH—, or*—O—CH₂—CH₂—NH— which fragment is bound to the —C═C— fragment of thephenyl ring to which it is fused, wherein the asterisks indicate thebond which is attached to the carbon atom of the phenyl ring in paraposition to the group L. Such fragments may be substituted with

-   -   one oxo substituent attached to a carbon atom in alpha position        to an oxygen and/or a nitrogen atom (thus forming together with        a nitrogen an amide group; or, together with an oxygen an ester        group; or, in case both an oxygen and a nitrogen atom are        adjacent, a carbamate group); and/or    -   one C₁₋₃-alkyl (especially methyl) attached to a nitrogen atom        having a free valency; or    -   two fluoro substituents attached to the same carbon atom.

Particular examples of the fragment

are especially fragments:

wherein V represents a direct bond or —CH₂—; and W represents —CH₂—,—O—, or —(NR^(a))— wherein R^(a) represents hydrogen or C₁₋₃-alkyl(especially R^(a) represents methyl).

Preferred examples of fragments

are:

and further examples are:

wherein in the groups above R^(a) independently represents hydrogen orC₁₋₃-alkyl (especially R^(a) represents methyl).

The term “aryl”, used alone or in combination, means phenyl or naphthyl,especially phenyl. The above-mentioned aryl groups are unsubstituted orsubstituted as explicitly defined.

The term “heteroaryl”, used alone or in combination, means a 5- to10-membered monocyclic or bicyclic aromatic ring containing one to amaximum of four heteroatoms, each independently selected from oxygen,nitrogen and sulfur. Examples of such heteroaryl groups are the5-membered heteroaryl groups furanyl, oxazolyl, isoxazolyl, oxadiazolyl,thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl; the 6-membered heteroaryl groups pyridinyl,pyrimidinyl, pyridazinyl, pyrazinyl; and the 8- to 10-membered bicyclicheteroaryl groups indolyl, isoindolyl, benzofuranyl, isobenzofuranyl,benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl,benzoxadiazolyl, benzothiadiazolyl, quinolinyl, isoquinolinyl,naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl,pyrrolopyrazinyl, imidazopyridinyl, imidazopyridazinyl, andimidazothiazolyl. The above-mentioned heteroaryl groups areunsubstituted or substituted as explicitly defined.

The term “di-(C₁₋₃-alkyl)amino” refers to a group —N(C₁₋₃-alkyl)₂wherein the two C₁₋₃-alkyl groups are independently selected. An exampleis dimethylamino.

Whenever the word “between” is used to describe a numerical range, it isto be understood that the end points of the indicated range areexplicitly included in the range. For example: if a temperature range isdescribed to be between 40° C. and 80° C., this means that the endpoints 40° C. and 80° C. are included in the range; or if a variable isdefined as being an integer between 1 and 4, this means that thevariable is the integer 1, 2, 3, or 4.

Unless used regarding temperatures, the term “about” placed before anumerical value “X” refers in the current application to an intervalextending from X minus 10% of X to X plus 10% of X, and preferably to aninterval extending from X minus 5% of X to X plus 5% of X. In theparticular case of temperatures, the term “about” placed before atemperature “Y” refers in the current application to an intervalextending from the temperature Y minus 10° C. to Y plus 10° C., andpreferably to an interval extending from Y minus 5° C. to Y plus 5° C.Besides, the term “room temperature” as used herein refers to atemperature of about 25° C.

Further embodiments of the invention are presented hereinafter:

2) A second embodiment of the invention relates to the compounds offormula (I) according to embodiment 1), wherein the fragment

represents a fragment:

wherein V represents a direct bond or —CH₂—; and W represents —CH₂—,—O—, or —(NR^(a))— wherein R^(a) represents hydrogen or C₁₋₃-alkyl(especially R^(a) represents methyl);wherein in a preferred sub-embodiment, said fragment is a group selectedfrom:

wherein R^(a) represents hydrogen, or C₁₋₃-alkyl (especially R^(a)represents methyl).

3) A further embodiment relates to compounds according to embodiment 1),wherein the fragment

represents

4) A further embodiment relates to compounds according to embodiment 1),wherein the fragment

represents

5) A further embodiment relates to compounds according to any one ofembodiments 1) to 4), wherein L represents —NH—CO—* wherein the asterisk(*) indicates the bond that is linked to the benzoxazole/thebenzothiazole moiety.

6) A further embodiment relates to compounds according to any one ofembodiments 1) to 4), wherein L represents —CO—NH—*, wherein theasterisk (*) indicates the bond that is linked to the benzoxazole/thebenzothiazole moiety.

7) A further embodiment relates to compounds according to any one ofembodiments 1) to 6), wherein X represents O.

8) A further embodiment relates to compounds according to any one ofembodiments 1) to 6), wherein X represents S.

9) A further embodiment relates to compounds according to any one ofembodiments 1) to 8), wherein Y represents

-   -   —NR¹R² wherein        -   R¹ represents            -   C₁₋₄-alkyl (especially methyl, ethyl);            -   C₂₋₄-alkyl which is mono-substituted with                di-(C₁₋₃-alkyl)amino;            -   C₃₋₅-cycloalkyl-L¹-, wherein L¹ represents a direct bond                or C₁₋₃-alkylene (especially methylene); and wherein the                C₃₋₅-cycloalkyl optionally contains one oxygen ring                atom, and wherein said C₃₋₅-cycloalkyl is unsubstituted,                or mono-substituted with methyl or fluoro (especially                such group C₃₋₅-cycloalkyl-L¹- is oxetan-3-yl,                oxetan-3-yl-methyl, 3-methyl-oxetan-3-yl,                (3-fluoro-oxetan-3-yl)-methyl); or            -   1-(oxetan-3-yl)-piperidin-4-yl; and        -   R² represents hydrogen, C₁₋₃-alkyl (especially methyl,            ethyl), or C₃₋₅-cycloalkyl (especially cyclopropyl);    -   or Y represents a saturated 4- to 7-membered monocyclic        heterocyclyl selected from:        -   morpholin-4-yl; 2-oxo-pyrrolidin-1-yl;            1,1-dioxidothiomorpholin-4-yl; or piperazin-1-yl optionally            mono-substituted in position 4 with oxetan-3-yl or            C₁₋₃-alkyl (especially methyl);        -   or azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl;            wherein said azetidin-1-yl, pyrrolidin-1-yl, or            piperidin-1-yl independently is unsubstituted, or            substituted with:            -   two fluoro substituents attached to the same ring carbon                atom; or            -   one phenyl or pyridinyl substituent, wherein said phenyl                or pyridinyl is unsubstituted; or            -   one substituent selected from hydroxy; C₁₋₃-alkoxy                (especially methoxy, isopropoxy); —CO—C₁₋₄-alkoxy                (especially (tert.-butyl-oxy)-carbonyl);                di-(C₁₋₃-alkyl)amino (especially dimethylamino); and                C₁₋₃-alkyl which is mono-substituted with                di-(C₁₋₃-alkyl)amino, hydroxy, or C₁₋₃-alkoxy                (especially dimethylamino-methyl,                1-hydroxy-1-methyl-ethyl, ethoxy-methyl); or            -   two substituents, wherein one of said substituents is                C₁₋₄-alkyl (especially methyl), and the other is                independently selected from hydroxy, or                di-(C₁₋₃-alkyl)amino (especially dimethylamino) (wherein                especially said two substituents are attached to the                same ring carbon atom of said heterocyclic group); or            -   one substituent selected from morpholin-4-yl;                1,1-dioxidothiomorpholin-4-yl;            -   one substituent selected from azetidin-1-yl,                pyrrolidin-1-yl, or piperidin-1-yl; wherein said groups                independently are unsubstituted, or mono-substituted                with hydroxy, or di-substituted with methyl and hydroxy                (wherein especially both substituents are attached to                the same ring carbon atom of said group);    -   or Y represents saturated 7- to 11-membered spiro-bicyclic        heterocyclyl (especially a 7- to 10-membered spiro-bicyclic        heterocyclyl) containing at least one nitrogen atom, wherein        said nitrogen atom is bound to the benzoxazole/the benzothiazole        moiety, and wherein said heterocyclyl optionally contains        (especially in the distant ring of said spiro-bicyclic        heterocyclyl) one further ring heteroatom independently selected        from oxygen, nitrogen and sulfur; wherein said heterocyclyl is        unsubstituted, or substituted with:        -   two oxo substituents at a ring sulfur ring atom (thus            forming a —SO₂— group); or        -   one C₁₋₃-alkyl substituent (especially methyl) attached to a            ring nitrogen atom having a free valency.

10) A further embodiment relates to compounds according to any one ofembodiments 1) to 8), wherein

Y represents a group —NR¹R², wherein

-   -   R¹ represents        -   C₁₋₄-alkyl (especially methyl, ethyl);        -   C₂₋₄-alkyl which is mono-substituted with            di-(C₁₋₃-alkyl)amino;        -   C₃₋₅-cycloalkyl-L¹-, wherein L¹ represents a direct bond or            C₁₋₃-alkylene (especially methylene); and wherein the            C₃₋₅-cycloalkyl optionally contains one oxygen ring atom,            and wherein said C₃₋₅-cycloalkyl is unsubstituted, or            mono-substituted with methyl or fluoro (especially such            group C₃₋₅-cycloalkyl-L¹- is oxetan-3-yl,            oxetan-3-yl-methyl, 3-methyl-oxetan-3-yl,            (3-fluoro-oxetan-3-yl)-methyl); or        -   1-(oxetan-3-yl)-piperidin-4-yl; and    -   R² represents hydrogen, C₁₋₃-alkyl (especially methyl, ethyl),        or C₃₋₅-cycloalkyl (especially cyclopropyl);        or Y represents a group

wherein

-   -   r and q both represent the integer 2; and    -   Z represents O, SO₂, or NR^(Y1), wherein R^(Y1) represents        oxetan-3-yl or C₁₋₃-alkyl (especially methyl);        or    -   r represents the integer 0, 1, 2, or 3; q represents the integer        1, 2, 3, or 4; and the sum of r and q is 2, 3, or 4;    -   Z represents CH₂, CHR^(Y2), or CR^(Y3)R^(Y4);    -   wherein        -   R^(Y2) represents            -   unsubstituted phenyl, or unsubstituted 5- or 6-membered                heteroaryl (especially unsubstituted phenyl);            -   hydroxy; C₁₋₃-alkoxy (especially methoxy, isopropoxy);                —CO—C₁₋₄-alkoxy (especially tert.-butyl-oxy-carbonyl);                di-(C₁₋₃-alkyl)amino (especially dimethylamino); or                C₁₋₃-alkyl which is mono-substituted with                di-(C₁₋₃-alkyl)amino, hydroxy, or C₁₋₃-alkoxy                (especially dimethylamino-methyl,                1-hydroxy-1-methyl-ethyl, ethoxy-methyl);            -   morpholin-4-yl; 1,1-dioxidothiomorpholin-4-yl; or                piperazin-1-yl which is optionally mono-substituted in                position 4 with C₁₋₃-alkyl (especially methyl); or            -   azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl;                wherein said groups independently are unsubstituted, or                mono-substituted with hydroxy, or di-substituted with                methyl and hydroxy (wherein especially both substituents                are attached to the same ring carbon atom of said                group);        -   and        -   R^(Y3) represents C₁₋₄-alkyl (especially methyl); and R^(Y4)            independently represents hydroxy, or di-(C₁₋₃-alkyl)amino            (especially dimethylamino);        -   or R^(Y3) and R^(Y4) both represent fluoro;        -   or R^(Y3) and R^(Y4) together with the carbon atom to which            they are attached to form            -   a 4- to 6-membered saturated carbocyclic ring; or            -   a 4- to 6-membered saturated heterocyclic ring, wherein                said heterocyclic ring contains one ring heteroatom                independently selected from oxygen, nitrogen and sulfur;                and wherein said heterocyclic ring is unsubstituted, or                substituted with:                -   two oxo substituents at a ring sulfur ring atom                    (thus forming a —SO₂— group); or                -   one C₁₋₃-alkyl substituent (especially methyl)                    attached to a ring nitrogen atom having a free                    valency.

11) A further embodiment relates to compounds according to any one ofembodiments 1) to 8), wherein Y represents

-   -   N—(C₁₋₃-alkyl)amino, N,N-di-(C₁₋₃-alkyl)-amino,        N-[2-(di-C₁₋₃-alkyl)amino)-ethyl]-N—(C₁₋₃-alkyl)-amino,        N—(C₁₋₄-alkyl)-N-(oxetan-3-yl)-amino,        N—(C₃₋₅-cycloalkyl)-N-(oxetan-3-yl)-amino,        N—(C₁₋₄-alkyl)-N-(oxetan-3-yl-methyl)-amino,        N-(3-methyl-oxetan-3-yl)-N-methylamino,        N-(3-fluoro-oxetan-3-yl-methyl)-N-methylamino, or        N-methyl-((N-(oxetan-3-yl)-piperidin)-4-yl)-amino;    -   or Y represents a saturated 4- to 7-membered monocyclic        heterocyclyl selected from:        -   morpholin-4-yl; 2-oxo-pyrrolidin-1-yl;            1,1-dioxidothiomorpholin-4-yl; or piperazin-1-yl optionally            mono-substituted in position 4 with oxetan-3-yl or            C₁₋₃-alkyl (especially methyl);        -   or azetidin-1-yl which is unsubstituted, or substituted            with:            -   two fluoro substituents attached to the same ring carbon                atom; or            -   one phenyl or pyridinyl substituent, wherein said phenyl                or pyridinyl is unsubstituted; or            -   one substituent selected from hydroxy; C₁₋₃-alkoxy                (especially isopropoxy); —CO—C₁₋₄-alkoxy (especially                (tert.-butyl-oxy)-carbonyl); di-(C₁₋₃-alkyl)amino                (especially dimethylamino); and C₁₋₃-alkyl which is                mono-substituted with di-(C₁₋₃-alkyl)amino, hydroxy, or                C₁₋₃-alkoxy (especially dimethylamino-methyl,                1-hydroxy-1-methyl-ethyl, ethoxy-methyl); or            -   two substituents, wherein one of said substituents is                C₁₋₄-alkyl (especially methyl), and the other is                independently selected from hydroxy, or                di-(C₁₋₃-alkyl)amino (especially dimethylamino) (wherein                especially said two substituents are attached to the                same ring carbon atom of said heterocyclic group); or            -   one substituent selected from morpholin-4-yl;                1,1-dioxidothiomorpholin-4-yl;            -   one substituent selected from azetidin-1-yl,                pyrrolidin-1-yl, or piperidin-1-yl; wherein said groups                independently are unsubstituted, or mono-substituted                with hydroxy, or di-substituted with methyl and hydroxy                (wherein especially both substituents are attached to                the same ring carbon atom of said group);        -   or pyrrolidin-1-yl, or piperidin-1-yl; wherein said            pyrrolidin-1-yl, or piperidin-1-yl independently is            unsubstituted, or substituted with:            -   two fluoro substituents attached to the same ring carbon                atom; or            -   one substituent selected from hydroxy; C₁₋₃-alkoxy                (especially methoxy); di-(C₁₋₃-alkyl)amino (especially                dimethylamino); and C₁₋₃-alkyl which is mono-substituted                with di-(C₁₋₃-alkyl)amino, or C₁₋₃-alkoxy (especially                dimethylamino-methyl, ethoxy-methyl);    -   or Y represents saturated 7- to 11-membered spiro-bicyclic        heterocyclyl (especially a 7- to 10-membered spiro-bicyclic        heterocyclyl) containing at least one nitrogen atom, wherein        said nitrogen atom is bound to the benzoxazole/the benzothiazole        moiety, and wherein said heterocyclyl optionally contains        (especially in the distant ring of said spiro-bicyclic        heterocyclyl) one further ring heteroatom independently selected        from oxygen, nitrogen and sulfur; wherein said heterocyclyl is        unsubstituted, or substituted with:        -   two oxo substituents at a ring sulfur ring atom (thus            forming a —SO₂— group); or        -   one C₁₋₃-alkyl substituent (especially methyl) attached to a            ring nitrogen atom having a free valency.

12) A further embodiment relates to compounds according to any one ofembodiments 1) to 8), wherein Y represents

-   -   saturated 4- to 7-membered monocyclic heterocyclyl selected        from:        -   morpholin-4-yl; 2-oxo-pyrrolidin-1-yl;            1,1-dioxidothiomorpholin-4-yl; or piperazin-1-yl optionally            mono-substituted in position 4 with oxetan-3-yl or            C₁₋₃-alkyl (especially methyl);        -   or azetidin-1-yl which is unsubstituted, or substituted            with:            -   two fluoro substituents attached to the same ring carbon                atom; or            -   one phenyl substituent, wherein said phenyl is                unsubstituted; or            -   one substituent selected from hydroxy; C₁₋₃-alkoxy                (especially isopropoxy); —CO—C₁₋₄-alkoxy (especially                (tert.-butyl-oxy)-carbonyl); di-(C₁₋₃-alkyl)amino                (especially dimethylamino); and C₁₋₃-alkyl which is                mono-substituted with di-(C₁₋₃-alkyl)amino, hydroxy, or                C₁₋₃-alkoxy (especially dimethylamino-methyl,                1-hydroxy-1-methyl-ethyl, ethoxy-methyl); or            -   two substituents, wherein one of said substituents is                C₁₋₄-alkyl (especially methyl), and the other is                independently selected from hydroxy, or                di-(C₁₋₃-alkyl)amino (especially dimethylamino) (wherein                especially said two substituents are attached to the                same ring carbon atom of said heterocyclic group); or            -   one substituent selected from morpholin-4-yl;                1,1-dioxidothiomorpholin-4-yl;            -   one substituent selected from azetidin-1-yl,                pyrrolidin-1-yl, or piperidin-1-yl; wherein said groups                independently are unsubstituted, or mono-substituted                with hydroxy, or di-substituted with methyl and hydroxy                (wherein especially both substituents are attached to                the same ring carbon atom of said group);        -   or pyrrolidin-1-yl, or piperidin-1-yl; wherein said            pyrrolidin-1-yl, or piperidin-1-yl independently is            unsubstituted, or substituted with:            -   two fluoro substituents attached to the same ring carbon                atom; or            -   one substituent selected from hydroxy; C₁₋₃-alkoxy                (especially methoxy); di-(C₁₋₃-alkyl)amino (especially                dimethylamino); and C₁₋₃-alkyl which is mono-substituted                with di-(C₁₋₃-alkyl)amino, or C₁₋₃-alkoxy (especially                dimethylamino-methyl, ethoxy-methyl);    -   or Y represents saturated 7- to 11-membered spiro-bicyclic        heterocyclyl (especially a 7- to 10-membered spiro-bicyclic        heterocyclyl) containing at least one nitrogen atom, wherein        said nitrogen atom is bound to the benzoxazole/the benzothiazole        moiety, and wherein said heterocyclyl optionally contains        (especially in the distant ring of said spiro-bicyclic        heterocyclyl) one further ring heteroatom independently selected        from oxygen, nitrogen and sulfur; wherein said heterocyclyl is        unsubstituted, or substituted with:        -   two oxo substituents at a ring sulfur ring atom (thus            forming a —SO₂— group); or        -   one C₁₋₃-alkyl substituent (especially methyl) attached to a            ring nitrogen atom having a free valency.

13) A further embodiment relates to compounds according to any one ofembodiments 1) to 8), wherein Y represents a group independentlyselected from the following groups A), B), C), D), or E):

14) A further embodiment relates to compounds according to any one ofembodiments 1) to 8), wherein Y represents a group independentlyselected from the following groups A), B), C), or D):

15) A further embodiment relates to compounds according to any one ofembodiments 1) to 8), wherein Y represents a group independentlyselected from the following groups A) or B):

16) The invention, thus, relates to compounds of the formula (I) asdefined in embodiment 1), or to such compounds further limited by thecharacteristics of any one of embodiments 2) to 14), under considerationof their respective dependencies; to pharmaceutically acceptable saltsthereof; and to the use of such compounds as medicaments, especially forthe prevention or treatment of diseases or disorders associated withimpaired ROS production, and/or for the prevention or treatment ofvarious fibrotic diseases. Especially the following embodiments relatingto the compounds of formula (I) are thus possible and intended andherewith specifically disclosed in individualized form: 1, 2+1, 3+1,4+1, 5+1, 5+2+1, 5+3+1, 5+4+1, 6+1, 6+2+1, 6+3+1, 6+4+1, 7+1, 7+2+1,7+3+1, 7+4+1, 7+5+1, 7+5+2+1, 7+5+3+1, 7+5+4+1, 7+6+1, 7+6+2+1, 7+6+3+1,7+6+4+1, 8+1, 8+2+1, 8+3+1, 8+4+1, 8+5+1, 8+5+2+1, 8+5+3+1, 8+5+4+1,8+6+1, 8+6+2+1, 8+6+3+1, 8+6+4+1, 9+1, 9+2+1, 9+3+1, 9+4+1, 9+5+1,9+5+2+1, 9+5+3+1, 9+5+4+1, 9+6+1, 9+6+2+1, 9+6+3+1, 9+6+4+1, 9+7+1,9+7+2+1, 9+7+3+1, 9+7+4+1, 9+7+5+1, 9+7+5+2+1, 9+7+5+3+1, 9+7+5+4+1,9+7+6+1, 9+7+6+2+1, 9+7+6+3+1, 9+7+6+4+1, 9+8+1, 9+8+2+1, 9+8+3+1,9+8+4+1, 9+8+5+1, 9+8+5+2+1, 9+8+5+3+1, 9+8+5+4+1, 9+8+6+1, 9+8+6+2+1,9+8+6+3+1, 9+8+6+4+1, 10+1, 10+2+1, 10+3+1, 10+4+1, 10+5+1, 10+5+2+1,10+5+3+1, 10+5+4+1, 10+6+1, 10+6+2+1, 10+6+3+1, 10+6+4+1, 10+7+1,10+7+2+1, 10+7+3+1, 10+7+4+1, 10+7+5+1, 10+7+5+2+1, 10+7+5+3+1,10+7+5+4+1, 10+7+6+1, 10+7+6+2+1, 10+7+6+3+1, 10+7+6+4+1, 10+8+1,10+8+2+1, 10+8+3+1, 10+8+4+1, 10+8+5+1, 10+8+5+2+1, 10+8+5+3+1,10+8+5+4+1, 10+8+6+1, 10+8+6+2+1, 10+8+6+3+1, 10+8+6+4+1, 11+1, 11+2+1,11+3+1, 11+4+1, 11+5+1, 11+5+2+1, 11+5+3+1, 11+5+4+1, 11+6+1, 11+6+2+1,11+6+3+1, 11+6+4+1, 11+7+1, 11+7+2+1, 11+7+3+1, 11+7+4+1, 11+7+5+1,11+7+5+2+1, 11+7+5+3+1, 11+7+5+4+1, 11+7+6+1, 11+7+6+2+1, 11+7+6+3+1,11+7+6+4+1, 11+8+1, 11+8+2+1, 11+8+3+1, 11+8+4+1, 11+8+5+1, 11+8+5+2+1,11+8+5+3+1, 11+8+5+4+1, 11+8+6+1, 11+8+6+2+1, 11+8+6+3+1, 11+8+6+4+1,12+1, 12+2+1, 12+3+1, 12+4+1, 12+5+1, 12+5+2+1, 12+5+3+1, 12+5+4+1,12+6+1, 12+6+2+1, 12+6+3+1, 12+6+4+1, 12+7+1, 12+7+2+1, 12+7+3+1,12+7+4+1, 12+7+5+1, 12+7+5+2+1, 12+7+5+3+1, 12+7+5+4+1, 12+7+6+1,12+7+6+2+1, 12+7+6+3+1, 12+7+6+4+1, 12+8+1, 12+8+2+1, 12+8+3+1,12+8+4+1, 12+8+5+1, 12+8+5+2+1, 12+8+5+3+1, 12+8+5+4+1, 12+8+6+1,12+8+6+2+1, 12+8+6+3+1, 12+8+6+4+1, 13+1, 13+2+1, 13+3+1, 13+4+1,13+5+1, 13+5+2+1, 13+5+3+1, 13+5+4+1, 13+6+1, 13+6+2+1, 13+6+3+1,13+6+4+1, 13+7+1, 13+7+2+1, 13+7+3+1, 13+7+4+1, 13+7+5+1, 13+7+5+2+1,13+7+5+3+1, 13+7+5+4+1, 13+7+6+1, 13+7+6+2+1, 13+7+6+3+1, 13+7+6+4+1,13+8+1, 13+8+2+1, 13+8+3+1, 13+8+4+1, 13+8+5+1, 13+8+5+2+1, 13+8+5+3+1,13+8+5+4+1, 13+8+6+1, 13+8+6+2+1, 13+8+6+3+1, 13+8+6+4+1, 14+1, 14+2+1,14+3+1, 14+4+1, 14+5+1, 14+5+2+1, 14+5+3+1, 14+5+4+1, 14+6+1, 14+6+2+1,14+6+3+1, 14+6+4+1, 14+7+1, 14+7+2+1, 14+7+3+1, 14+7+4+1, 14+7+5+1,14+7+5+2+1, 14+7+5+3+1, 14+7+5+4+1, 14+7+6+1, 14+7+6+2+1, 14+7+6+3+1,14+7+6+4+1, 14+8+1, 14+8+2+1, 14+8+3+1, 14+8+4+1, 14+8+5+1, 14+8+5+2+1,14+8+5+3+1, 14+8+5+4+1, 14+8+6+1, 14+8+6+2+1, 14+8+6+3+1, 14+8+6+4+1,15+1, 15+2+1, 15+3+1, 15+4+1, 15+5+1, 15+5+2+1, 15+5+3+1, 15+5+4+1,15+6+1, 15+6+2+1, 15+6+3+1, 15+6+4+1, 15+7+1, 15+7+2+1, 15+7+3+1,15+7+4+1, 15+7+5+1, 15+7+5+2+1, 15+7+5+3+1, 15+7+5+4+1, 15+7+6+1,15+7+6+2+1, 15+7+6+3+1, 15+7+6+4+1, 15+8+1, 15+8+2+1, 15+8+3+1,15+8+4+1, 15+8+5+1, 15+8+5+2+1, 15+8+5+3+1, 15+8+5+4+1, 15+8+6+1,15+8+6+2+1, 15+8+6+3+1, 15+8+6+4+1.

In the list above, the numbers refer to the embodiments according totheir numbering provided hereinabove whereas “+” indicates thedependency from another embodiment. The different individualizedembodiments are separated by commas. In other words, “14+8+1” forexample refers to embodiment 14) depending on embodiment 8), dependingon embodiment 1), i.e. embodiment “14+8+1” corresponds to the compoundsof embodiment 1) further limited by the features of the embodiments 8)and 14).

17) A further embodiment relates to compounds of Formula (I) accordingto embodiment 1) which are selected from the following compounds:

-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(1,1-dioxo-1l6-thiomorpholin-4-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    (2-piperidin-1-yl-benzooxazol-5-yl)-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    (2-pyrrolidin-1-yl-benzooxazol-5-yl)-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(4-methyl-piperazin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    (2-morpholin-4-yl-benzooxazol-5-yl)-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    (2-diethylamino-benzooxazol-5-yl)-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(4,4-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(3,3-difluoro-azetidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(3,3-difluoro-pyrrolidin-1-yl)-benzooxazol-5-yl]amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(3-methoxy-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(4-methoxy-piperidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(3-hydroxy-3-methyl-azetidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(4-dimethylamino-piperidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(3,3-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(3-morpholin-4-yl-azetidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    {2-[methyl-(3-methyl-oxetan-3-yl)-amino]-benzooxazol-5-yl}-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    {2-[3-(1,1-dioxo-1l6-thiomorpholin-4-yl)-azetidin-1-yl]-benzooxazol-5-yl}-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(3-hydroxy-3-methyl-[1,3]biazetidinyl-1′-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(1-oxa-6-aza-spiro[3.3]hept-6-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(2-oxa-6-aza-spiro[3.4]oct-6-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(6-oxa-2-aza-spiro[3.5]non-2-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(1-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(2-oxa-5-aza-spiro[3.5]non-5-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(1-oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(1-oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(1-oxa-8-aza-spiro[4.5]dec-8-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(7-oxa-2-aza-spiro[3.5]non-2-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(5-oxa-2-aza-spiro[3.4]oct-2-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    {2-[3-(4-hydroxy-piperidin-1-yl)-azetidin-1-yl]-benzooxazol-5-yl}-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(6-methyl-2,6-diaza-spiro[3.5]non-2-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(5-oxa-2-aza-spiro[3.5]non-2-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(7-oxa-1-aza-spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide;-   1-{5-[(2,3-Dihydro-benzofuran-5-carbonyl)-amino]-benzooxazol-2-yl}-azetidine-3-carboxylic    acid tert-butyl ester;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(2-oxo-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid    [2-(1,1-dioxo-thiomorpholin-4-yl)-benzooxazol-5-yl]-amide;-   Chroman-6-carboxylic acid    [2-(1,1-dioxo-thiomorpholin-4-yl)-benzooxazol-5-yl]amide;-   4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid    [2-(1,1-dioxo-thiomorpholin-4-yl)-benzooxazol-5-yl]-amide;-   (R)—N-(2-(3-hydroxypiperidin-1-yl)benzo[d]oxazol-5-yl)-2,3-dihydrobenzofuran-5-carboxamide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-((S)-3-hydroxy-piperidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(3-isopropoxy-azetidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-((R)-3-hydroxy-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-((S)-3-hydroxy-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(3-hydroxy-azetidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(4-hydroxy-piperidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(3-phenyl-azetidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(2-ethoxymethyl-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    {2-[(3-fluoro-oxetan-3-ylmethyl)-methyl-amino]-benzooxazol-5-yl}-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(4-oxetan-3-yl-piperazin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    {2-[methyl-(1-oxetan-3-yl-piperidin-4-yl)-amino]-benzooxazol-5-yl}-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(methyl-oxetan-3-ylmethyl-amino)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(methyl-oxetan-3-yl-amino)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(2-methoxymethyl-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(3-methoxy-piperidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(3-dimethylaminomethyl-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(2-phenyl-azetidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(cyclopropyl-oxetan-3-yl-amino)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(3-pyrrolidin-1-yl-azetidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    {2-[3-(1-hydroxy-1-methyl-ethyl)-azetidin-1-yl]-benzooxazol-5-yl}-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(3-dimethylaminomethyl-azetidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(7-methyl-1,7-diaza-spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(7-methyl-2,7-diaza-spiro[3.5]non-2-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(3-dimethylamino-azetidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(2,2-dioxo-2l6-thia-6-aza-spiro[3.3]hept-6-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(1,1-dioxo-1l6-thia-6-aza-spiro[3.3]hept-6-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(3-dimethylamino-3-methyl-azetidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(6-oxa-2-aza-spiro[3.4]oct-2-yl)-benzooxazol-5-yl]-amide;-   2-(4-Methyl-piperazin-1-yl)-benzooxazole-5-carboxylic acid    (2,3-dihydro-benzofuran-5-yl)-amide;-   2-Piperidin 1 yl benzooxazole-5-carboxylic acid    (2,3-dihydro-benzofuran-5-yl)-amide;-   2-Morpholin-4-yl-benzooxazole-5-carboxylic acid    (2,3-dihydro-benzofuran-5-yl)-amide;-   2-Diethylamino-benzooxazole-5-carboxylic acid    (2,3-dihydro-benzofuran-5-yl)-amide;-   2-Pyrrolidin-1-yl-benzooxazole-5-carboxylic acid    (2,3-dihydro-benzofuran-5-yl)-amide;-   2-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazole-5-carboxylic acid    (2,3-dihydro-benzofuran-5-yl)-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    (2-piperidin-1-yl-benzothiazol-5-yl)-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    (2-morpholin-4-yl-benzothiazol-5-yl)-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(4-methyl-piperazin-1-yl)-benzothiazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid (2-pyrrolidin 1 yl    benzothiazol-5-yl)-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    (2-diethylamino-benzothiazol-5-yl)-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    (2-dimethylamino-benzothiazol-5-yl)-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(3,3-difluoro-azetidin-1-yl)-benzothiazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(3,3-difluoro-pyrrolidin-1-yl)-benzothiazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(3,3-difluoro-piperidin-1-yl)-benzothiazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzothiazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-benzothiazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(1,1-dioxo-1l6-thiomorpholin-4-yl)-benzothiazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(3-methoxy-pyrrolidin-1-yl)-benzothiazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(4-methoxy-piperidin-1-yl)-benzothiazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(3-hydroxy-3-methyl-azetidin-1-yl)-benzothiazol-5-yl]-amide;-   (S)—N-(2-(3-hydroxypyrrolidin-1-yl)benzo[d]thiazol-5-yl)-2,3-dihydrobenzofuran-5-carboxamide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-benzothiazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    {2-[methyl-(1-oxetan-3-yl-piperidin-4-yl)-amino]-benzothiazol-5-yl}-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzothiazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(methyl-oxetan-3-yl-amino)-benzothiazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(3-methoxy-piperidin-1-yl)-benzothiazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(3-hydroxy-azetidin-1-yl)-benzothiazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(4-hydroxy-piperidin-1-yl)-benzothiazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(2-phenyl-azetidin-1-yl)-benzothiazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-((R)-3-hydroxy-pyrrolidin-1-yl)-benzothiazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(2-methoxymethyl-pyrrolidin-1-yl)-benzothiazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-((S)-3-hydroxy-piperidin-1-yl)-benzothiazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(2-oxa-6-aza-spiro[3.4]oct-6-yl)-benzothiazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-((R)-3-hydroxy-piperidin-1-yl)-benzothiazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    [2-(2-dimethylaminomethyl-pyrrolidin-1-yl)-benzothiazol-5-yl]-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    (2-azetidin-1-yl-benzooxazol-5-yl)-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid    (2-ethylamino-benzooxazol-5-yl)-amide;-   2,3-Dihydro-benzofuran-5-carboxylic acid [2-(3-pyridin 2 yl    azetidin-1-yl)-benzooxazol-5-yl]-amide;-   Benzo[1,3]dioxole-5-carboxylic acid    [2-(3-hydroxy-azetidin-1-yl)-benzooxazol-5-yl]-amide;-   Benzo[1,3]dioxole-5-carboxylic acid    [2-(1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide;-   Benzo[1,3]dioxole-5-carboxylic acid    [2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide;-   Benzo[1,3]dioxole-5-carboxylic acid    [2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)-benzooxazol-5-yl]-amide;-   Benzo[1,3]dioxole-5-carboxylic acid    [2-(7-oxa-1-aza-spiro[3.5]non-1-yl)-benzooxazol-5-yl]amide;-   Benzo[1,3]dioxole-5-carboxylic acid    (2-pyrrolidin-1-yl-benzooxazol-5-yl)-amide;-   Benzo[1,3]dioxole-5-carboxylic acid    [2-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-benzooxazol-5-yl]-amide;-   Benzo[1,3]dioxole-5-carboxylic acid (2-piperidin 1 yl    benzooxazol-5-yl)-amide;-   Benzo[1,3]dioxole-5-carboxylic acid    [2-(3,3-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide;-   Benzo[1,3]dioxole-5-carboxylic acid    [2-(4-methoxy-piperidin-1-yl)-benzooxazol-5-yl]-amide;-   Benzo[1,3]dioxole-5-carboxylic acid    [2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol-5-yl]-amide;-   Benzo[1,3]dioxole-5-carboxylic acid    [2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol-5-yl]-amide;-   Benzo[1,3]dioxole-5-carboxylic acid    [2-(4,4-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide;-   Benzo[1,3]dioxole-5-carboxylic acid    [2-(4-hydroxy-piperidin-1-yl)-benzooxazol-5-yl]-amide;-   Benzo[1,3]dioxole-5-carboxylic acid    (2-morpholin-4-yl-benzooxazol-5-yl)-amide;-   Benzo[1,3]dioxole-5-carboxylic acid    [2-(4-methyl-piperazin-1-yl)-benzooxazol-5-yl]-amide;-   Benzo[1,3]dioxole-5-carboxylic acid    [2-(cyclopropyl-oxetan-3-yl-amino)-benzooxazol-5-yl]-amide;-   Benzo[1,3]dioxole-5-carboxylic acid    (2-diethylamino-benzooxazol-5-yl)-amide;-   Chroman-6-carboxylic acid    [2-(3-hydroxy-azetidin-1-yl)-benzooxazol-5-yl]-amide;-   Chroman-6-carboxylic acid    [2-(1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide;-   Chroman-6-carboxylic acid    [2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide;-   Chroman-6-carboxylic acid    [2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)-benzooxazol-5-yl]-amide;-   Chroman-6-carboxylic acid    [2-(7-oxa-1-aza-spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide;-   Chroman-6-carboxylic acid    (2-pyrrolidin-1-yl-benzooxazol-5-yl)-amide;-   Chroman-6-carboxylic acid    [2-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-benzooxazol-5-yl]-amide;-   Chroman-6-carboxylic acid (2-piperidin-1-yl-benzooxazol-5-yl)-amide;-   Chroman-6-carboxylic acid    [2-(4,4-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide;-   Chroman-6-carboxylic acid    [2-(3,3-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide;-   Chroman-6-carboxylic acid    [2-(4-hydroxy-piperidin-1-yl)-benzooxazol-5-yl]-amide;-   Chroman-6-carboxylic acid    [2-(4-methoxy-piperidin-1-yl)-benzooxazol-5-yl]-amide;-   Chroman-6-carboxylic acid    [2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol-5-yl]-amide;-   Chroman-6-carboxylic acid    [2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol-5-yl]-amide;-   Chroman-6-carboxylic acid (2-morpholin 4 yl benzooxazol-5-yl)-amide;-   Chroman-6-carboxylic acid    [2-(4-methyl-piperazin-1-yl)-benzooxazol-5-yl]-amide;-   Chroman-6-carboxylic acid (2-diethylamino-benzooxazol-5-yl)-amide;-   Chroman-6-carboxylic acid    [2-(cyclopropyl-oxetan-3-yl-amino)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid    [2-(3-hydroxy-azetidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid    [2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid    [2-(1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid    [2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid    [2-(7-oxa-1-aza-spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid    (2-pyrrolidin-1-yl-benzooxazol-5-yl)-amide;-   2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid    [2-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid    (2-piperidin-1-yl-benzooxazol-5-yl)-amide;-   2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid    [2-(4-hydroxy-piperidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid    [2-(3,3-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid    [2-(4-methoxy-piperidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid    [2-(4,4-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid    [2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid    (2-morpholin-4-yl-benzooxazol-5-yl)-amide;-   2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid    [2-(4-methyl-piperazin-1-yl)-benzooxazol-5-yl]-amide;-   2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid    (2-diethylamino-benzooxazol-5-yl)-amide;-   2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid    [2-(cyclopropyl-oxetan-3-yl-amino)-benzooxazol-5-yl]-amide;-   4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid    [2-(1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide;-   4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid    [2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide;-   4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid    [2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)-benzooxazol-5-yl]-amide;-   4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid    [2-(7-oxa-1-aza-spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide;-   4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid    [2-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-benzooxazol-5-yl]-amide;-   4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid    (2-piperidin-1-yl-benzooxazol-5-yl)-amide;-   4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid    [2-(4-hydroxy-piperidin-1-yl)-benzooxazol-5-yl]-amide;-   4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid    [2-(4,4-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide;-   4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid    [2-(3,3-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide;-   4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid    [2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol-5-yl]-amide;-   4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid    [2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol-5-yl]-amide;-   4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid    [2-(4-methoxy-piperidin-1-yl)-benzooxazol-5-yl]-amide;-   4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid    (2-morpholin 4 yl benzooxazol-5-yl)-amide;-   4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid    [2-(4-methyl-piperazin-1-yl)-benzooxazol-5-yl]-amide;-   4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid    (2-diethylamino-benzooxazol-5-yl)-amide;-   4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid    [2-(cyclopropyl-oxetan-3-yl-amino)-benzooxazol-5-yl]-amide;-   2-Piperidin-1-yl-benzothiazole-5-carboxylic acid    (2,3-dihydro-benzofuran-5-yl)-amide;-   2-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)-benzothiazole-5-carboxylic acid    (2,3-dihydro-benzofuran-5-yl)-amide;-   2-(4-Methoxy-piperidin-1-yl)-benzothiazole-5-carboxylic acid    (2,3-dihydro-benzofuran-5-yl)-amide;-   2-(4-Methyl-piperazin-1-yl)-benzothiazole-5-carboxylic acid    (2,3-dihydro-benzofuran-5-yl)-amide;-   2-(6-Oxa-1-aza-spiro[3.4]oct-1-yl)-benzothiazole-5-carboxylic acid    (2,3-dihydro-benzofuran-5-yl)-amide;-   2-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)-benzothiazole-5-carboxylic acid    (2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide;-   2-(6-Oxa-1-aza-spiro[3.4]oct-1-yl)-benzothiazole-5-carboxylic acid    (2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide; and-   2-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)-benzothiazole-5-carboxylic acid    benzo[1,3]dioxol-5-ylamide.

The compounds of compounds of formula (I) as defined in any one ofembodiments 1) to 17) and their pharmaceutically acceptable salts can beused as medicaments, e.g. in the form of pharmaceutical compositions forenteral (such especially oral, e.g. in form of a tablet or capsule) orparenteral administration (including intravenous, intraperitoneal,subcutaneous, or topical application, or inhalation).

The production of the pharmaceutical compositions can be effected in amanner which will be familiar to any person skilled in the art (see forexample Remington, The Science and Practice of Pharmacy, 21st Edition(2005), Part 5, “Pharmaceutical Manufacturing” [published by LippincottWilliams & Wilkins]) by bringing the described compounds of Formula (I)or their pharmaceutically acceptable salts, optionally in combinationwith other therapeutically valuable substances, into a galenicaladministration form together with suitable, non-toxic, inert,pharmaceutically acceptable solid or liquid carrier materials and, ifdesired, usual pharmaceutical adjuvants.

The compounds of compounds of formula (I) as defined in any one ofembodiments 1) to 17) and their pharmaceutically acceptable salts areuseful for modulating NOX4, especially for the prevention or treatmentof fibrotic diseases; and/or diseases or disorders associated with animpaired reactive oxygen species (ROS) production.

Fibrotic diseases may defined as comprising pulmonary fibrosis,especially idiopathic pulmonary fibrosis (IPF); scleroderma, especiallysystemic sclerosis; pancreatic fibrosis; liver fibrosis; chronic kidneydisease, especially diabetic nephropathy; and cardiomyopathy (associatedwith fibrosis) including heart failure resulting from chroniccardiomyopathy, diabetic cardiomyopathy, and hypertrophiccardiomyopathy.

Diseases or disorders associated with impaired reactive oxygen species(ROS) production may defined as comprising pulmonary hypertension;hypertension; asthma; acute respiratory distress syndrome (ARDS);myocardial infarction; acute heart failure; cardiac and skeletalmyopathy including Barth syndrome; stroke; traumatic brain injury;neuropathic pain; ataxia telangiectasia (Louis-Bar syndrome); oculardiseases, such as diabetic renopathy; and cancer (especially ovariancancer, renal cell carcinoma, glioblastoma multiforme, head and necksquamous cell carcinoma (HNSCC), pancreatic adenocarcinoma, coloncancer, urothelial cancer, prostate cancer, breast cancer, non-smallcell lung cancer, and metastasis).

In particular, diseases or disorders associated with impaired reactiveoxygen species (ROS) production may defined as comprising heart andvascular remodeling in response to pulmonary hypertension; hypertension;asthma; acute respiratory distress syndrome (ARDS); acute myocardialinfarction; acute heart failure; heart failure associated withuncontrolled neurohormonal excitation; cardiac and skeletal myopathyincluding Barth syndrome; acute stroke; and acute traumatic braininjury.

For avoidance of any doubt, if compounds are described as being usefulfor the prevention or treatment of certain diseases, such compounds arelikewise suitable for use in the preparation of a medicament for theprevention or treatment of said diseases.

The present invention also relates to a method for the prevention ortreatment of a disease or disorder mentioned herein comprisingadministering to a subject in need thereof a pharmaceutically activeamount of a compound of formula (I) as defined in any one ofembodiments 1) to 17).

In a preferred embodiment of the invention, the administered amount ofsuch a compound of formula (I) as defined in any one of embodiments 1)to 17) is comprised between 1 mg and 1000 mg per day, particularlybetween 5 mg and 500 mg per day, more particularly between 10 mg and 400mg per day.

The present invention also relates to a method of inhibition ofmyofibroblast differentiation in a subject (by modulating NOX4),comprising administering to said subject an effective amount of acompound of formula (I) as defined in any one of embodiments 1) to 17);wherein especially said subject has been diagnosed to have a fibroticdisease, and/or a disease or disorder associated with impaired reactiveoxygen species (ROS) production.

Said inhibition of myofibroblast differentiation may especially bemonitored by

-   -   reduced levels of ROS in organ biopsies (Gorin, Y., et al.        Targeting NADPH oxidase with a novel dual NOX1/NOX4 inhibitor        attenuates renal pathology in type 1 diabetes. Am J Physiol        Renal Physiol, ajprenal 00396 02014 (2015)); and/or    -   reduced levels of ROS in exhaled breath condensate (Psathakis,        K., et al. Exhaled markers of oxidative stress in idiopathic        pulmonary fibrosis. Eur J Clin Invest 36, 362-367 (2006));        and/or    -   reduced levels of alpha smooth muscle actin; and/or    -   reduced levels of deposited extracellular matrix protein in        tissue biopsies (Hecker, L., et al. NADPH oxidase-4 mediates        myofibroblast activation and fibrogenic responses to lung        injury. Nat Med 15, 1077-1081 (2009));        of said subject (e.g. when compared to the respective levels        before said subject has been administered the compound of        formula (I)).

The present invention also relates to the use of a compound of Formula(I) for the preparation of a pharmaceutical composition, optionally foruse in combination with one or several anti-fibrotic agents [such as,but not limited to kinase inhibitors (more specifically: receptortyrosine kinase antagonists and/or p38 kinase inhibitors), and/orantagonists of the renin-angiotensin system (RAS), and/or endothelinreceptor antagonists, and or stimulators of guanylate cyclase, and/orligands of peroxisome proliferator activated nuclear receptor gamma(PPARc), and/or antagonists of serotonin signalling, and/or antagonistsof integrin-mediated signalling, and/or antagonists of cytokinesignalling, and/or antagonists of lysophosphatidic acid (LPA) receptors,and/or therapies targeting M2 type macrophage biology-for the preventionor treatment of the diseases and disorders mentioned herein.

Preparation of the Compounds of Formula (I)

The compounds of Formula (I) can be manufactured by the methods givenbelow, by the methods given in the Examples or by analogous methods.Optimum reaction conditions may vary with the particular reactants orsolvents used, but such conditions can be determined by a person skilledin the art by routine optimisation procedures.

Compounds of the Formula (I) of the present invention can be preparedaccording to the general sequence of reactions outlined below, by knownliterature methods, by the methods given in the experimental part or byanalogous methods. Only a few of the synthetic possibilities leading tocompounds of Formula (I) are described. Optimum reaction conditions mayvary with the particular reactants or solvents used, but such conditionscan be determined by a person skilled in the art by routine optimisationprocedures. In some instances the generic groups L, Y, and ring (A) maybe incompatible with the assembly illustrated in the schemes below andwill require the use of protecting groups. The use of protecting groupsis well known in the art (see for example “Protective Groups in OrganicSynthesis”, T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999). Forthe purposes of this discussion, it will be assumed that such protectinggroups as necessary are in place. The compounds obtained may also beconverted into pharmaceutically acceptable salts thereof in a mannerknown per se. In the general sequence of reactions outlined below, thegeneric groups L, X, Y, and ring (A) are as defined for formula (I).

Compounds of Formula (I) wherein L represents —CO—NH— are prepared byreacting a compound of Structure 1 with a compound of Structure 2 byusing a coupling reagent such as HATU, TBTU, EDC, etc. in the presenceor absence of HOBt, in the presence of a base such Et₃N, DIPEA, etc. andin a solvent such as DMF, DCM, THF, etc. Alternatively, coupling of acompound of Structure 1 to a compound of Structure 2 may also beaffected by reacting the corresponding acid chloride of a compound ofStructure 1.

Compounds of Structure 1 are either commercially available or areprepared according to procedures know to the person skilled in the art.

Compounds of Structure 2 are prepared by reducing a compound ofStructure 3 e.g. with a hydrogen gas in the presence of a catalyst suchas Pd/C, Pt/C, PtO₂ in a solvent such as MeOH, EtOH, EA, THF, etc. ormixtures thereof, or with Fe in a solvent such as acetic acid.

Compounds of Structure 3 are prepared by reacting a compound ofStructure 4 with a compound of Structure 5 in the presence or absence ofa base such as Et₃N, DIPEA, NaHCO₃, K₂CO₃, KOtBu, etc. in a solvent suchas THF, DMF, DMSO, etc. or in analogy to literature procedures (e.g. R.E. Martin et al. Bioorg. Med. Chem. Lett. 19 (2009) 6106-6113; F. Hayatet al. Bull. Korean Chem. Soc. 34 (2013) 495-499).

Compounds of Structure 4 are either commercially available or areprepared by reacting a compound of Structure 6 with a chlorinating agentsuch as SOCl₂, SO₂Cl₂, POCl₃, or PCl₅ in the presence or absence of asolvent such as DCM, CHCl₃, DMF, etc. preferrably at temperaturesbetween 20 and 80° C.

Compounds of Structure 5 are either commercially available or areprepared according to procedures known to a person skilled in the art.

Compounds of structure 6 are either commercially available or areprepared according to known literature procedures e.g. L. Zhu et al. J.Heterocycl. Chem. 42 (2005) 727-730, J. C. Mannion et al. WO2011/112602;G. M. Wynne et al. WO2007/091106.

Alternatively, compounds of Formula (I) wherein L represents —CO—NH—*may also be prepared by reacting a compound of structure 7 wherein Lrepresents —CO—NH—* with a compound of structure 5 in the presence orabsence of a base such as Et₃N, DIPEA, NaHCO₃, K₂CO₃, KOtBu, etc. in asolvent such as THF, DMF, DMSO, etc.

Compounds of structure 7 are prepared by treating a compound ofstructure 8 wherein L represents —CO—NH—* with a chlorinating reagentsuch as SOCl₂, in presence or absence of a solvent such as DCM, DMF, orDMA.

Compounds of structure 8 can be prepared by reacting a compound ofstructure 10 with a compound of structure 9 with a base such as Et₃N,DIPEA, etc., in a solvent such as DCM, or by reacting a compound ofstructure 10 with a compound of structure 1 in the presence of a baseand in the presence of a coupling reagent such as TBTU, HATU, EDC, etc.in a solvent such as DMF. A compound of structure 10 can also be reactedwith a compound of structure 1 by chlorinating a compound structure 1 insitu in the presence of a chlorinating agent such as SOCl₂ in thepresence or absence of a catalytic amount of DMF in a solvent such asDCM.

Compounds of structure 9 are either commercially available or may beprepared from a compound of structure 1 following known procedures.

Compounds of structure 10 are either commercially available or areprepared according to known procedures, e.g. L. Katz et al. J. Org.Chem. 19 (1954) 758-766, K. D. Rynearson, Bioorg. Med. Chem. Lett. 24(2014) 3521-3525, D. S. B. Ongarora et al. Bioorg. Med. Chem. Lett. 22(2012) 5046-5050, L. Zhu et al. J. Heterocycl. Chem. 42 (2005) 727-730,Y. Murti et al. J. Pharm. Res. 7 (2008) 153-155.

Compounds of Formula (I) wherein L represents —NH—CO—* are prepared byreacting a compound of Structure 11 with a compound of Structure 12 byusing a coupling reagent such as 1-chloro-N,N-2-trimethylpropenylamine(Ghosez' reagent), HATU, TBTU, EDC, or POCl₃ etc. in the presence orabsence of HOBt, in the presence of a base such Et₃N, DIPEA, etc. and ina solvent such as DCM, DMF, THF, pyridine, or mixtures thereof.Alternatively, coupling of a compound of Structure 11 to a compound ofStructure 12 may also be achieved by reacting the corresponding acidchloride of a compound of Structure 12 with a compound of Structure 11.

Compounds of Structure 11 are commercially available or well known inthe art.

Compounds of Structure 12 are prepared by saponification of Structure13, wherein R represents C₁₋₄-alkyl, under conditions know to a personskilled in the art, e.g. by exposing a compound of structure 13 to amixture of aq. NaOH, methanol and THF or to aq. HCl.

Compounds of Structure 13 are prepared by reacting a compound ofStructure 14 with a compound of Structure 5 in the presence or absenceof a base such as Et₃N, DIPEA, NaHCO₃, K₂CO₃, KOtBu, etc. in a solventsuch as THF, DMF, DMSO, etc., preferrably at temperatures between 20 and80° C.

Compounds of Structure 14 are either commercially available or areprepared following literature procedures (e.g. A. Binggeli,WO2007025897), or by chlorinating a compound of Structure 15 with achlorinating agent such as POCl₃, PCl₅, SOCl₂, SO₂Cl₂ in a solvent suchas DCM, CHCl₃, DMF, etc.

Compounds of Structure 15 are either commercially available or areobtained following literature procedures (e.g. S. Hachiya, WO2008059854,J.-L. Chen WO2005086904).

EXPERIMENTAL PART

The following examples illustrate the invention but do not at all limitthe scope thereof.

All temperatures are stated in ° C. Compounds are characterized by¹H-NMR (Bruker Avance II, 400 MHz UltraShield™, 400 MHz (¹H), 100 MHz(¹³C); or Bruker Avance III HD, Ascend 500 MHz (H), 125 MHz (¹³C) magnetequipped with DCH cryoprobe); chemical shifts are given in ppm relativeto the solvent used; multiplicities: s=singlet, d=doublet, t=triplet,p=pentuplet, hex=hexet, hept=heptet, m=multiplet, br=broad, couplingconstants are given in Hz), in case non-deuterated DMSO was used as asolvent, the resonance of the solvent at 2.5 ppm was suppressed; byLC-MS: Finnigan MSQ™ plus or MSQ™ surveyor (Dionex, Switzerland), withHP 1100 Binary Pump and DAD (Agilent, Switzerland), column: ZorbaxSB-AQ, 5 μm, 120 Å, 4.6×50 mm (Agilent), gradient: 5-95% acetonitrile inwater containing 0.04% of trifluoroacetic acid, within 1 min, flow: 4.5mL/min; t_(R) is given in min, or by TLC (TLC-plates from Merck, Silicagel 60 F₂₅₄); or by melting point. Compounds are purified by preparativeHPLC (column: X-terra RP18, 50×19 mm, 5 gradient: 10-95% MeCN in watercontaining 0.5% of formic acid).

ABBREVIATIONS (AS USED HEREIN)

-   abs absolute-   aq. aqueous-   BSA bovine serum albumin-   CC column chromatography on silica gel-   DCM dichloromethane-   DIPEA Wining's base, diethylisopropylamine-   DMA N,N-dimethylacetamide-   DMF dimethylformamide-   DMSO dimethylsulfoxide-   EA ethyl acetate-   EDC N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide-   Et ethyl-   EtOH ethanol-   h hour(s)-   HATU    1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxid hexafluorophosphate-   HBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HOBt 1-hydroxy-benzotriazole-   HPLC high performance liquid chromatography-   HV high vacuum conditions-   LC-MS liquid chromatography-mass spectrometry-   KOtBu potassium tert.-butylate-   Lit. literature-   Me methyl-   MeCN acetonitrile-   MeOH methanol-   min minute(s)-   NEt₃ triethylamine-   org. organic-   PPh₃ triphenylphosphine-   PyBOP    benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium-hexafluoro-phosphate-   prep. preparative-   rt room temperature-   sat. saturated-   TBTU 2-(1H-benzotriazole-1-yl)-1,2,3,3-tetramethyluronium    tetrafluoroborate-   tert. tertiary-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TLC thin layer chromatography-   t_(R) retention time

Preparation of Building Blocks 5-Nitrobenzo[d]oxazole-2-thiol

To a solution of 2-amino-4-nitrophenol (10 g, 64.2 mmol) in abs. EtOH(150 mL) potassium ethyl xanthogenate (12.6 g, 77.1 mmol) was added. Themixture was stirred under reflux for 5 h before it was cooled to rt andconcetrated. The residue was dissolved in water (300 mL) and treatedwith 1 M aq. HCl (75 mL) with vigorous stirring. The precipitate thatformed was collected, washed with water (50 mL) and dried under HV for 2days to give the title compound (or tautomer) (11.9 g) as a grey-beigesolid; LC-MS: t_(R)=0.71 min; [M+H]⁺=not detectable; ¹H NMR (400 MHz,D₆-DMSO) δ: 14.33 (s br, 1H), 8.21 (dd, J₁=2.3 Hz, J₂=8.9 Hz, 1H), 7.96(d, J=2.3 Hz, 1H), 7.75 (d, J=8.9 Hz, 1H).

2-Chloro-5-nitrobenzo[d]oxazole

To a suspension of 5-nitrobenzo[d]oxazole-2-thiol (5.9 g, 30 mmol) inthionyl chloride (54.7 mL, 751 mmol) DMF (0.04 mL, 0.456 mmol) wasadded. The mixture was heated to 65° C. and stirred for 1 h. The mixturewas cooled to rt and concentrated. The residue was suspended in toluene(30 mL) and the solvent was again evaporated. The residue was then takenup in DCM (25 mL) and purified by CC eluting with heptane:EA 4:1 to givethe title compound (4.4 g) as a beige solid; LC-MS: t_(R)=0.78 min;[M+H]⁺=not detectable; ¹H NMR (400 MHz, CDCl₃) δ: 8.61 (d, J=2.3 Hz,1H), 8.38 (dd, J₁=2.3 Hz, J₂=9.0 Hz, 1H), 7.68 (d, J=9.0 Hz, 1H).

5-Nitrobenzo[d]oxazole-2-thiol

A mixture of 2-amino-4-nitrophenol (4.0 g, 26 mmol) and potassiumxanthogenate (5.0 g, 31.2 mmol) in EtOH (100 mL) was refluxed for 24 hbefore it was stirred at rt for two additional days. The precipitat thatformed was collected, washed with EtOH and dried to give the titlecompound (or tautomer) (5.3 g) as an orange solid; LC-MS: t_(R)=0.71min; [M+H]⁺=not detectable; ¹H NMR (400 MHz, D₆-DMSO) δ: 7.85 (dd,J₁=2.4 Hz, J₂=8.6 Hz, 1H), 7.82 (d, J=2.3 Hz, 1H), 7.28 (d, J=8.6 Hz,1H).

5-Aminobenzo[d]oxazole-2-thiol

To a suspension of 5-nitrobenzo[d]oxazole-2-thiol (1.0 g, 5.1 mmol) inEtOH (38 mL,) and H₂O (38 mL) at 80° C. was added NH₄Cl (545 mg, 10.2mmol), followed by Fe (1.40 g, 25 mmol). The resulting mixture wasstirred at 80° C. for 1.5 h. The mixture was cooled to rt, filtered andthe filtrate was concentrated. The precipitate that formed wascollected, washed with water and dried to give the title compound (ortautomer) (640 mg) as a beige powder; LC-MS: t_(R)=0.37 min;[M+H]⁺=208.06; ¹H NMR (400 MHz, D₆-DMSO) δ: 13.39 (s br, 1H), 7.13 (d,J=8.6 Hz, 1H), 6.36-6.51 (m, 2H), 5.26 (s br, 2H).

Methyl 2-mercaptobenzo[d]oxazole-5-carboxylate

To a solution of methyl 3-amino-5-hydroxybenzoate (1.0 g, 5.98 mmol) inMeOH (13.5 mL) KOH (468 mg, 7.18 mmol) was added. The mixture wasstirred at rt until all KOH had dissolved. Then CS₂ (9.02 mL, 150 mmol)was added and the mixture was stirred at 60° C. for 16 h before it wascooled to 0° C. and diluted with EA (50 mL). 1M aq. HCl (8.6 mL) wasadded to acidify the mixture to pH 1. The organic layer was separated,washed with water (25 mL), dried over MgSO₄, filtered and concentratedto give the title compound (or tautomer) (1.18 g) as a solid; LC-MS:t_(R)=0.72 min; [M+H]⁺=209.96; ¹H NMR (400 MHz, D₆-DMSO) δ: 14.14 (s,1H), 7.89 (dd, J₁=1.7 Hz, J₂=8.5 Hz, 1H), 7.69 (d, J=1.5 Hz, 1H), 7.63(d, J=8.5 Hz, 1H), 3.88 (s, 3H).

Methyl 2-chlorobenzo[d]oxazole-5-carboxylate

To a solution of methyl 2-mercaptobenzo[d]oxazole-5-carboxylate 1.08 g,5.16 mmol) in DCM (5.5 mL) POCl₃ (4.25 mL, 46.5 mmol) followed by PCl₅(1.29 g, 6.19 mmol) was added. The mixture was stirred at rt for 8 hbefore it was concentrated. The remaining oil was cooled with an icebath before sat. aq. NaHCO₃ solution (50 mL) was added. When theevolution of gas had ceased the mixture was transferred to a separatingfunnel and extracted twice with DCM (2×50 mL). The combined organicextracts were dried over MgSO₄, filtered and concentrated. The crudeproduct was suspended in diethyl ether (10 mL). The suspension wasstirred for 10 min before it was filtered. The filtrate was concentratedand dried to give the title compound (0.62 g) as a solid; LC-MS:t_(R)=0.80 min; [M+H+CH₃CN]⁺=253.04; ¹H NMR (400 MHz, CDCl₃) δ: 8.40 (d,J=1.2 Hz, 1H), 8.15 (dd, J₁=1.6 Hz, J₂=8.7 Hz, 1H), 7.58 (d, J=8.6 Hz,1H), 3.99 (s, 3H).

5-Nitrobenzo[d]thiazole-2-thiol

To a solution of 2-fluoro-5-nitroaniline (3.12 g, 20 mmol) in DMF (15mL) potassium ethyl xanthogenate (3.93 g, 24 mmol) was added. Themixture was stirred at 100° C. for 5 h before it was cooled to rt,diluted with water (25 mL) and 1 M aq. HCl (35 mL). The precipitate thatformed was collected, washed with water (15 mL) and dried to give thetitle compound (or tautomer) (3.99 g) as a beige solid; LC-MS:t_(R)=0.76 min; [M+H]⁺=not detectable; ¹H NMR (400 MHz, D₆-DMSO) δ:14.17 (s, 1H), 8.15 (dd, J, =2.2 Hz, J₂=8.8 Hz, 1H), 7.99 (d, J=9.0 Hz),7.97 (d, J=2.3 Hz).

2-Chloro-5-nitrobenzo[d]thiazole

Solid 5-nitrobenzo[d]thiazole-2-thiol (4.0 g, 18.8 mmol) was placed in around bottom flask and cooled to 0° C. while SO₂Cl₂ (9.1 mL, 113 mmol)was slowly added at 0° C. Upon complete additions, the yellow suspensionwas stirred at 0° C. for 5 min, then at rt for 2 h. The mixture waspoured onto ice/water (200 mL) and stirred for 1 h. The precipitate thatformed was collected, washed with water and dried under high vacuum. Thematerial was slurried in EA (25 mL), vigorously stirred for 15 min andfiltered. The filtrate was concentrated and dried. The obtained solidabsorbed to silica gel and purified by CC eluting with heptane:EA 4:1 togive the title compound (2.02 g) as a solid; LC-MS: t_(R)=0.84 min;[M+H]⁺=214.51; ¹H NMR (400 MHz, CDCl₃) δ: 8.84 (d, J=2.2 Hz, 1H), 8.35(dd, J₁=2.2 Hz, J₂=8.9 Hz, 1H), 7.98 (d, J=8.9 Hz, 1H).

2-Chlorobenzo[d]thiazol-5-amine

To a solution of 2-chloro-5-nitrobenzo[d]thiazole (2.18 g, 10.2 mmol) inEtOH:acetic acid 91:9 (102 mL) iron powder (5.70 g, 102 mmol) wascarefully added. The mixture was refluxed for 1.5 h before it wasfiltered. The filtrate was concentrated to about one third of the volumeand the pH of the solution was adjusted to pH 8 by adding 10% aq. NaOHsolution. The mixture was extracted with EA (150 mL). The organicextract was washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude product was suspended in EtOH (4 mL), filtered,washed with additional EtOH (0.5 mL) and dried to give the titlecompound (1.55 g) as a solid; LC-MS: t_(R)=0.78 min; [M+H]⁺=185.03; ¹HNMR (400 MHz, D₆-DMSO) δ: 7.65 (d, J=8.7 Hz, 1H), 7.06 (d, J=1.9 Hz,1H), 6.79 (dd, J₁=2.0 Hz, J₂=8.7 Hz, 1H), 5.43 (s, 2H).

2-Chloro-benzothiazole-5-carbonyl chloride

To a mixture of 2-sulfanyl-1,3-benzothiazole-5-carboxylic acid (50.1 mg,0.237 mmol), PCl₅ (158 mg, 0.745 mmol) and POCl₃ (0.446 mL, 4.74 mmol),DMF (0.042 mL, 0.524 mmol) was carefully added. The mixture became warmand the thick suspension was stirred at rt for 3 h to become a clearsolution. The mixture was concentrated and diluted with DCM, solidmaterial was filtered off and the filtrate was concentrated and dried togive the crude title compound (92 mg) as a pale yellow resin which wasused without further purification; LC-MS: t_(R)=0.91 min; [M+H]⁺=notdetectable.

Preparation of Intermediates Intermediate A14-(5-Aminobenzo[d]oxazol-2-yl)thiomorpholine 1,1-dioxide

a) To a solution of 2-chloro-5-nitrobenzo[d]oxazole (1.0 g, 5.0 mmol)and Et₃N (2.1 mL, 15.1 mmol) in THF (25 mL) thiomorpholine 1,1-dioxide(715 mg, 5.29 mmol) was added. The mixture was stirred at 70° C. for 3 hbefore it was diluted with water (100 mL) and extracted with EA (200 mL)followed by DCM (100 mL). The combined org. extracts were dried overMgSO₄, filtered and concentrated. The remaining solid was suspended inDCM (10 mL), filtered off, washed with additional DCM (5 mL) and driedto give a first batch of the title compound (698 mg). The filtrate wasconcentrated and once more suspended in DCM (2 mL). Solid material wascollected, washed with a small amount of DCM and dried to give a secondbatch of the title compound (460 mg). The obtained solid materials werecombined; LC-MS: t_(R)=0.69 min; [M+H]⁺=297.98; ¹H NMR (400 MHz,D₆-DMSO) δ: 8.15 (d, J=2.3 Hz, 1H), 8.04 (dd, J₁=2.3 Hz, J₂=8.8 Hz, 1H),7/1 (d, J=8.8 Hz, 1H), 4.08-4.16 (m, 4H), 3.35-3.42 (m, 4H).

b) To a solution of 4-(5-nitrobenzo[d]oxazol-2-yl)thiomorpholine1,1-dioxide (1.10 g, 3.7 mmol) in acetic acid (25 mL) iron powder (2.07g, 37 mmol) was added carefully. The mixture was stirred at 40° C. for 2h before it was filtered. The filtrate is diluted with water (50 mL) andthe pH was adjusted to 13-14 by adding 5 M aq. NaOH solution. Themixture was extracted twice with DCM (2×100 mL), the combined org.extracts were dried over MgSO₄, filtered and dried to give the titlecompound (908 mg) as a grey solid; LC-MS: t_(R)=0.38 min; [M+H]⁺=268.07;¹H NMR (400 MHz, D₆-DMSO) δ: 7.07 (d, J=8.5 Hz, 1H), 6.53 (d, J=2.1 Hz,1H), 6.28 (dd, J₁=2.2 Hz, J₂=8.5 Hz, 1H), 4.84 (s, 2H), 3.98-4.05 (m,4H), 3.26-3.32 (m, 4H). or alternatively:

b) To a mixture of 4-(5-nitrobenzo[d]oxazol-2-yl)thiomorpholine1,1-dioxide (10 mg, 0.05 mmol) in degassed EA (0.5 mL) wet Pd/C (10 mg)was added before it was stirred under 4 bar of H2 at rt for 16 h. Thecatalyst was removed by filtration and the filtrate was concentrated anddried to give the title compound (5 mg).

Intermediates A2 to A38

The following 5-amino-benzo[d]oxazol derivatives were obtained inanalogy to Intermediate A1:

Inter- LC-MS mediate Name t_(R) [min] [M + H]⁺ A22-(piperidin-1-yl)benzo[d]oxazol-5-amine 0.52 218.31 A32-(pyrrolidin-1-yl)benzo[d]oxazol-5-amine 0.46 204.29 A42-(4-methylpiperazin-1- 0.17 233.29 yl)benzo[d]oxazol-5-amine A52-morpholinobenzo[d]oxazol-5-amine 0.42 220.30 A6N²,N²-diethylbenzo[d]oxazole-2,5-diamine 0.50 206.27 A72-(2-oxa-6-azaspiro[3.3]heptan- 0.42 232.24 6-yl)benzo[d]oxazol-5-amineA8 2-(4,4-difluoropiperidin-1- 0.54 254.24 yl)benzo[d]oxazol-5-amine A92-(3,3-difluoroazetidin-1- 0.46 267.26* yl)benzo[d]oxazol-5-amine A102-(3,3-difluoropyrrolidin-1- 0.50 240.24 yl)benzo[d]oxazol-5-amine A112-(3-methoxypyrrolidin-1- 0.45 234.12 yl)benzo[d]oxazol-5-amine A122-(4-methoxypiperidin-1- 0.49 248.29 yl)benzo[d]oxazol-5-amine A131-(5-aminobenzo[d]oxazol-2- 0.40 220.24 yl)-3-methylazetidin-3-ol A14N²-(2-(dimethylamino)ethyl)-N²- 0.18 234.93methylbenzo[d]oxazole-2,5-diamine A15 2-(4-(dimethylamino)piperidin-1-0.29 261.33 yl)benzo[d]oxazol-5-amine A162-(6-oxa-1-azaspiro[3.3]heptan-1- 0.42 232.24 yl)benzo[d]oxazol-5-amineA17 2-(3,3-difluoropiperidin-1- 0.53 254.26 yl)benzo[d]oxazol-5-amineA18 2-(3-morpholinoazetidin-1- 0.24 275.16 yl)benzo[d]oxazol-5-amine A19N²-methyl-N²-(3-methyloxetan-3- 0.45 234.24yl)benzo[d]oxazole-2,5-diamine A204-(1-(5-aminobenzo[d]oxazol-2-yl)azetidin- 0.43 323.003-yl)thiomorpholine 1,1-dioxide A21 1′-(5-aminobenzo[d]oxazol-2-yl)-3-0.24 275.05 methyl-[1,3′-biazetidin]-3-ol A222-(1-oxa-6-azaspiro[3.3]heptan-6- 0.44 232.11 yl)benzo[d]oxazol-5-amineA23 2-(2-oxa-6-azaspiro[3.4]octan-6- 0.44 246.15yl)benzo[d]oxazol-5-amine A24 2-(6-oxa-2-azaspiro[3.5]nonan-2- 0.50260.15 yl)benzo[d]oxazol-5-amine A25 2-(2-oxa-5-azaspiro[3.4]octan-5-0.45 246.14 yl)benzo[d]oxazol-5-amine A262-(1-oxa-6-azaspiro[3.5]nonan-6- 0.46 260.15 yl)benzo[d]oxazol-5-amineA27 2-(2-oxa-5-azaspiro[3.5]nonan-5- 0.49 260.15yl)benzo[d]oxazol-5-amine A28 2-(1-oxa-7-azaspiro[3.5]nonan-7- 0.47260.16 yl)benzo[d]oxazol-5-amine A29 2-(8-oxa-2-azaspiro[4.5]decan-2-0.49 274.16 yl)benzo[d]oxazol-5-amine A302-(1-oxa-8-azaspiro[4.5]decan-8- 0.53 274.16 yl)benzo[d]oxazol-5-amineA31 2-(7-oxa-2-azaspiro[3.5]nonan-2- 0.48 260.16yl)benzo[d]oxazol-5-amine A32 2-(5-oxa-2-azaspiro[3.4]octan-2- 0.48246.15 yl)benzo[d]oxazol-5-amine A33 1-(1-(5-aminobenzo[d]oxazol-2- 0.20289.15 yl)azetidin-3-yl)piperidin-4-ol A342-(6-methyl-2,6-diazaspiro[3.5]nonan- 0.34 273.182-yl)benzo[d]oxazol-5-amine A35 2-(5-oxa-2-azaspiro[3.5]nonan-2- 0.52260.15 yl)benzo[d]oxazol-5-amine A36 2-(1-azaspiro[3.3]heptan-1- 0.55230.18 yl)benzo[d]oxazol-5-amine A37 2-(7-oxa-1-azaspiro[3.5]nonan-1-0.48 260.16 yl)benzo[d]oxazol-5-amine A38 tert-butyl1-(5-aminobenzo[d]oxazol-2- 0.60 290.15 yl)azetidine-3-carboxylate*represents [M + H + CH₃CN]⁺.

Intermediate A5: ¹H NMR (500 MHz, D₆-DMSO) δ: 7.04 (d, J=8.4 Hz, 1H),6.50 (d, J=2.1 Hz, 1H), 6.25 (dd, J, =2.2 Hz, J₂=8.4 Hz, 1H), 4.81 (s,2H), 3.67-3.73 (m, 4H), 3.48-3.55 (m, 4H).

Intermediate A39 1-(5-Aminobenzo[d]oxazol-2-yl)pyrrolidin-2-one

a) To a solution of 2-chloro-5-nitrobenzo[d]oxazole (800 mg, 4.03 mmol)in DCM (25 mL) were added ethyl 4-aminobutyrate hydrochloride (810 mg,4.83 mmol) followed by DIPEA (1.59 mL, 9.27 mmol) at 0° C. The mixturewas stirred at rt overnight before it was concentrated in vacuo, dilutedwith EA, washed with brine, dried over MgSO₄, filtered and concentrated.The crude product was purified by CC eluting with heptane:EA 1:1 to giveethyl 4-((5-nitrobenzo[d]oxazol-2-yl)amino)butanoate (1.01 g) as ayellow powder, LC-MS: t_(R)=0.77 min; [M+H]⁺=294.1.

b) A suspension of ethyl 4-((5-nitrobenzo[d]oxazol-2-yl)amino)butanoate(1.01 g, 3.44 mmol) in EtOH (20 mL) and 1M aq. NaOH (5.2 mL) was stirredat rt overnight before it was cooled with an ice bath. 1 M aq. HCl wasadded (5.2 mL) and the mixture was concentrated and dried to give crude4-((5-nitrobenzo[d]oxazol-2-yl)amino)butanoic acid (1.22 g) as a yellowpowder, LC-MS: t_(R)=0.60 min; [M+H]⁺=266.14. This material wasdissolved in DCM (25 mL) and SOCl₂ (0.89 mL, 12.1 mmol) was added. Themixture was stirred at rt for 2 h before it was concentrated in vacuo,dissolved in pyridine (10 mL) and stirred at rt for 1 h. The mixture wasagain concentrated, diluted with DCM and washed with brine. The organicextract was separated and the precipitate that formed was removed byfiltration (unreacted SM). The filtrate was dried over MgSO₄, filteredand concentrated. The crude product was first purified by CC elutingwith DCM:MeOH 10:1, then by prep. HPLC to give1-(5-nitrobenzo[d]oxazol-2-yl)pyrrolidin-2-one (133 mg) as a whitesolid, LC-MS: t_(R)=0.64 min; [M+H]⁺=248.11; ¹H NMR (400 MHz, CDCl₃) δ:8.50 (d, J=2.3 Hz, 1H), 8.25 (dd, J₁=2.3 Hz, J₂=8.9 Hz, 1H), 7.65 (d,J=8.8 Hz, 1H), 4.17-4.23 (m, 2H), 2.76 (t, J=7.9 Hz, 2H), 2.30-2.39 (m,2H).

c) To a solution of 1-(5-nitrobenzo[d]oxazol-2-yl)pyrrolidin-2-one (133mg, 0.538 mmol) in EA (2 mL) Pd/C (7 mg, 10% Pd, 50% wet) was added. Themixture was stirred under 1 bar of H₂ at rt for 18 h before the catalystwas removed by filtration. The filtrate was concentrated and dried togive 1-(5-aminobenzo[d]oxazol-2-yl)pyrrolidin-2-one (105 mg) as a whitesolid, LC-MS: t_(R)=0.32 min; [M+H]⁺=218.11.

Inter- LC-MS mediate Name t_(R) [min] [M + H]⁺ A402-Azetidin-1-yl-benzooxazol-5-ylamine 0.43 190.16 A411-(5-Amino-benzooxazol- 0.54 234.15 2-yl)-piperidin-4-ol A422-(2-Oxa-7-aza-spiro[3.5]non- 0.64 260.15 7-yl)-benzooxazol-5-ylamineA43 1-(5-Amino-benzooxazol-2- 0.50 206.15 yl)-azetidin-3-ol A44N²-Cyclopropyl-N²-oxetan-3-yl- 0.65 246.12 benzooxazole-2,5-diamine A452-(6-Oxa-1-aza-spiro[3.4]oct-1-yl)- 0.62 246.14 benzooxazol-5-ylamineA46 2-(2-Oxa-6-aza-spiro[3.5]non-6-yl)- 0.66 260.14benzooxazol-5-ylamine A47 N²-Ethyl-benzooxazole-2,5-diamine 0.36 178.18A48 2-(3-Pyridin-2-yl-azetidin-1-yl)- 0.38 267.08 benzooxazol-5-ylamine

Intermediate B1N-(2-Mercaptobenzo[d]oxazol-5-yl)-2,3-dihydrobenzofuran-5-carboxamide

To a mixture of 5-aminobenzo[d]oxazole-2-thiol (540 mg, 3.25 mmol) inpyridine (27 mL) was added 2,3-dihydrobenzofuran-5-carbonyl chloride(593 mg, 3.25 mmol) at rt. The reaction mixture was stirred at rt for1.5 h before another portion of 2,3-dihydrobenzofuran-5-carbonylchloride (30 mg, 0.16 mmol) was added. Stirring was continued at rt for1 h before the mixture was concentrated. The residue was treated withwater, the resulting suspension was sonicated before the solid materialwas collected by filtration, washed and dried to give the title compound(890 mg) as a pink solid; LC-MS: t_(R)=0.77 min; [M+H]⁺=312.97; ¹H NMR(400 MHz, D₆-DMSO) δ: 13.84 (s br, 1H), 10.21 (s, 1H), 7.93 (d, J=1.7Hz, 1H), 7.88 (s, 1H), 7.80 (dd, J₁=1.3 Hz, J₂=8.3 Hz, 1H), 7.55 (dd,J₁=1.8 Hz, J₂=8.8 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 6.90 (d, J=8.4 Hz,1H), 4.64 (t, J=8.8 Hz, 2H), 3.27 (t, J=8.8 Hz, 2H).

Intermediate C1 2-(4-methylpiperazin-1-yl)benzo[d]oxazole-5-carboxylicAcid

a) To a solution of methyl 2-chlorobenzo[d]oxazole-5-carboxylate (98.5mg, 465 μmol) in THF(1.5 mL) Et₃N (195 μL, 1.4 mmol) followed by1-methylpiperazine (63 μL, 559 μmol) was added. The mixture was stirredat 65° C. for 16 h before it was cooled to rt and concentrated. Theresidue was dissolved in CH₃CN (1 mL) and DMF (1 mL), filtered and thefiltrate was separated by prep. HPLC to give methyl2-(4-methylpiperazin-1-yl)benzo[d]oxazole-5-carboxylate (80 mg) as asolid; LC-MS: t_(R)=0.51 min; [M+H]⁺=276.16; ¹H NMR (400 MHz, CDCl₃) δ:8.04 (d, J=1.5 Hz, 1H), 7.83 (dd, J₁=1.7 Hz, J₂=8.4 Hz, 1H), 7.29 (d,J=8.3 Hz, 1H), 3.94 (s, 3H), 3.77-3.82 (m, 4H), 2.57-2.62 (m, 4H), 2.41(s, 3H).

b) To a solution of methyl2-(4-methylpiperazin-1-yl)benzo[d]oxazole-5-carboxylate (76 mg, 0.28mmol) in THF (1 mL) and MeOH (1 mL) a 1 M aq. solution of NaOH (0.55 mL)was added. The mixture was stirred at rt for 18 h before it wasneutralized by adding 1 M aq. HCl. The precipitate that formed wascollected and dried to give tht title compound (49 mg) as hydrochloridesalt as a white solid; LC-MS: t_(R)=0.43 min; [M+H]⁺=262.11; ¹H NMR (400MHz, DMSO) δ: 12.93 (s, 1H), 11.04 (s, 1H), 7.85 (d, J=1.5 Hz, 1H), 7.75(dd, J₁=1.7 Hz, J₂=8.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 4.21-4.37 (m,2H), 3.43-3.71 (m, 4H), 3.08-3.27 (m, 2H), 2.80 (s, 3H).

Intermediates C2 to C6

The following 2-aminobenzo[d]oxazole-5-carboxylic acid derivatives wereobtained in analogy to Intermediate C1:

Inter- LC-MS mediate Name t_(R) [min] [M + H]⁺ C22-Piperidin-1-yl-benzooxazole- 0.70 247.13 5-carboxylic acid C32-Morpholin-4-yl-benzooxazole- 0.61 249.11 5-carboxylic acid C42-Diethylamino-benzooxazole- 0.68 235.11 5-carboxylic acid C52-Pyrrolidin-1-yl-benzooxazole- 0.61 233.16 5-carboxylic acid C62-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)- 0.60 261.04benzooxazole-5-carboxylic acid

Intermediate C2: ¹H NMR (400 MHz, D₆-DMSO) δ: 12.82 (s, 1H), 7.76 (d,J=1.5 Hz, 1H), 7.66 (dd, J₁=1.7 Hz, J₂=8.3 Hz, 1H), 7.47 (d, J=8.3 Hz,1H), 3.59-3.65 (m, 4H), 1.57-1.68 (m, 6H).

Intermediate C3: ¹H NMR (400 MHz, D₆-DMSO) δ: 12.86 (s, 1H), 7.81 (d,J=1.6 Hz, 1H), 7.70 (dd, J₁=1.6 Hz, J₂=8.3 Hz, 1H), 7.51 (d, J=8.3 Hz,1H), 3.71-3.76 (m, 4H), 3.60-3.65 (m, 4H).

Intermediate C4: ¹H NMR (400 MHz, D₆-DMSO) δ: 12.80 (s, 1H), 7.76 (d,J=1.6 Hz, 1H), 7.65 (dd, J₁=1.7 Hz, J₂=8.3 Hz, 1H), 7.48 (d, J=8.3 Hz,1H), 3.56 (q, J=7.1 Hz, 4H), 1.22 (t, J=7.1 Hz, 7H).

Intermediate C5: ¹H NMR (400 MHz, D₆-DMSO) δ: 12.80 (s, 1H), 7.77 (d,J=1.6 Hz, 1H), 7.65 (dd, J₁=1.7 Hz, J₂=8.3 Hz, 1H), 7.48 (d, J=8.3 Hz,1H), 3.54-3.60 (m, 4H), 1.95-2.01 (m, 4H).

Intermediate C6: ¹H NMR (400 MHz, D₆-DMSO) δ: 12.88 (s, 1H), 7.87 (d,J=1.5 Hz, 1H), 7.72 (dd, J₁=1.7 Hz, J₂=8.3 Hz, 1H), 7.57 (d, J=8.4 Hz,1H), 5.22 (d, J=7.7 Hz, 2H), 4.67 (d, J=7.7 Hz, 2H), 4.04 (t, J=7.2 Hz,2H), 2.73 (t, J=7.3 Hz, 2H).

Intermediate D1 2-(Piperid in-1-yl)benzo[d]thiazol-5-amine

a) To a solution of 2-chloro-5-nitrobenzo[d]thiazole (200 mg, 931 μmol)in THF (1.5 mL) Et₃N (0.195 mL, 1.4 mmol) followed by piperidine (0.138mL, 1.4 mmol) was added. The mixture was stirred at 65° C. for 1 hbefore it was diluted with EA (50 mL) and washed with water (50 mL). Theorganic extract was dried over MgSO₄, filtered and concentrated to give5-nitro-2-(piperidin-1-yl)benzo[d]thiazole (250 mg) as a solid; LC-MS:t_(R)=0.92 min; [M+H]⁺=264.18.

b) To a solution of 5-nitro-2-(piperidin-1-yl)benzo[d]thiazole (245 mg,0.93 mmol) in EtOH (15 mL) Pd/C (125 mg, 10% Pd, 50% water wet) wasadded. The mixture was stirred under 1 atm of H₂ for 4 days before thecatalyst was removed by filtration and the filtrate was evaporated. Thecrude product was purified by prep. HPLC to give the title compound (73mg) as a solid; LC-MS: t_(R)=0.54 min; [M+H]⁺=234.17; ¹H NMR (400 MHz,CDCl₃) δ: 7.33 (d, J=8.3 Hz, 1H), 6.93 (d, J=2.2 Hz, 1H), 6.49 (dd,J₁=2.2 Hz, J₂=8.3 Hz, 1H), 3.77 (s br, 2H), 3.56-3.64 (m, 4H), 1.67-1.77(m, 6H).

Intermediates D2 to D17

The following 5-amino-benzo[d]thiazol derivatives were obtained inanalogy to Intermediate D1:

Inter- LC-MS mediate Name t_(R) [min] [M + H]⁺ D22-Morpholin-4-yl-benzothiazol-5-ylamine 0.46 236.16 D32-(4-Methyl-piperazin-1-yl)- 0.27 249.19 benzothiazol-5-ylamine D42-Pyrrolidin-1-yl-benzothiazol-5-ylamine 0.48 220.11 D5N2,N2-Diethyl-benzothiazole-2,5-diamine 0.52 222.13 D6N2,N2-Dimethyl-benzothiazole-2,5-diamine 0.42 194.12 D72-(3,3-Difluoro-azetidin-1-yl)- 0.52 241.95 benzothiazol-5-ylamine D82-(3,3-Difluoro-pyrrolidin-1-yl)- 0.54 256.10 benzothiazol-5-ylamine D92-(3,3-Difluoro-piperidin-1-yl)- 0.57 270.10 benzothiazol-5-ylamine D102-(6-Oxa-1-aza-spiro[3.3]hept-1- 0.47 248.12 yl)-benzothiazol-5-ylamineD11 2-(2-Oxa-6-aza-spiro[3.3]hept-6- 0.45 248.12yl)-benzothiazol-5-ylamine D12 2-(1,1-Dioxo-1I6-thiomorpholin- 0.43284.04 4-yl)-benzothiazol-5-ylamine D13 N2-(2-Dimethylamino-ethyl)-N2-0.33 251.15 methyl-benzothiazole-2,5-diamine D142-(3-Methoxy-pyrrolidin-1-yl)- 0.48 250.12 benzothiazol-5-ylamine D152-(4-Methoxy-piperidin-1-yl)- 0.52 264.15 benzothiazol-5-ylamine D161-(5-Amino-benzothiazol-2-yl)- 0.44 236.11 3-methyl-azetidin-3-ol D172-(4-Dimethylamino-piperidin- 0.35 277.14 1-yl)-benzothiazol-5-ylamine

Intermediate D2: ¹H NMR (400 MHz, CDCl₃) δ: 7.37 (d, J=8.3 Hz, 1H), 6.96(d, J=2.2 Hz, 1H), 6.54 (dd, J₁=2.2 Hz, J₂=8.3 Hz, 1H), 3.83-3.87 (m,4H), 3.60-3.66 (m, 4H).

Intermediate D3: ¹H NMR (400 MHz, CDCl₃) δ: 7.36 (d, J=8.3 Hz, 1H), 6.93(d, J=2.2 Hz, 1H), 6.52 (dd, J₁=2.2 Hz, J₂=8.3 Hz, 1H), 3.70 (s br, 2H),3.63-3.68 (m, 4H), 2.51-2.61 (m, 4H), 2.39 (s, 3H).

Intermediated D9: ¹H NMR (400 MHz, CDCl₃) δ: 7.36 (d, J=8.3 Hz, 1H),6.96 (d, J=2.2 Hz, 1H), 6.54 (dd, J₁=2.2 Hz, J₂=8.4 Hz, 1H), 3.88 (t,J=11.4 Hz, 2H), 3.62-3.68 (m, 2H), 2.07-2.19 (m, 2H), 1.92-2.00 (m, 2H).

Intermediate D10: ¹H NMR (400 MHz, CDCl₃) δ: 7.38 (d, J=8.4 Hz, 1H),7.09 (s, 1H), 6.57 (dd, =1.8 Hz, J₂=8.5 Hz, 1H), 5.48 (d, J=7.7 Hz, 2H),4.75 (d, J=7.7 Hz, 2H), 4.15 (t, J=7.2 Hz, 2H), 2.74 (t, J=7.4 Hz, 2H).

Intermediate E1N-(2-Chlorobenzo[d]thiazol-5-yl)-2,3-dihydrobenzofuran-5-carboxamide

To a solution of 2,3-dihydrobenzo[b]furan carboxylic acid (1.27 g, 7.5mmol) in DMF (22.5 mL) TBTU (2.48 g, 7.5 mmol) followed by DIPEA (3.93mL, 22.5 mmol) was added. The mixture was stirred at rt for 15 minbefore 2-chlorobenzo[d]thiazol-5-amine (1.52 g, 7.5 mmol) was added.Stirring is continued at 55° C. for 18 h. The mixture was concentrated,diluted with DCM (250 mL) and washed with sat. aq. NaHCO₃ solution (125mL). The organic extract was separated and concentrated. The crudeproduct was purified by CC eluting with a gradient of heptane:EE 1:2 topure EA to give the title compound (980 mg) as a solid; LC-MS*:t_(R)=1.01 min; [M+H]⁺=330.95 (*=0.5% NH₄OH instead of TFA in elutingsolvent.); ¹H NMR (400 MHz, DMSO) δ: 10.32 (s, 1H), 8.50 (d, J=1.9 Hz,1H), 8.04 (d, J=8.8 Hz, 1H), 7.92 (s, 1H), 7.87 (dd, =2.0 Hz, J₂=8.8 Hz,1H), 7.83 (dd, J₁=1.9 Hz, J₂=8.4 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 4.65(t, J=8.8 Hz, 2H), 3.28 (t, J=8.7 Hz, 2H).

Intermediate E22-Chloro-N-(2,3-dihydrobenzofuran-5-yl)benzo[d]thiazole-5-carboxamide

A solution of 2,3-dihydro-1-benzofuran-5-amine (33.7 mg, 0.237 mmol) andDIPEA (0.21 mL, 1.18 mmol) in DCM (1 mL) was cooled to 0° C. beforecrude 2-chloro-benzothiazole-5-carbonyl chloride (92 mg, 0.237 mmol)dissolved in DCM (1 mL) was added. The mixture was stirred at rt for 30min. The mixture was diluted with DCM (5 mL) and washed with water (5mL). the organic extract was dried over Na₂SO₄, filtered andconcentrated to give the crude title compound (69 mg) as a pale yellowresin; LC-MS: t_(R)=0.86 min; [M+H]⁺=330.97; ¹H NMR (400 MHz, D₆-DMSO):δ 10.28 (s, 1H), 8.56 (d, J=1.1 Hz, 1H), 8.26 (d, J=8.5 Hz, 1H), 8.07(dd, =1.5 Hz, J₂=8.5 Hz, 1H), 7.70 (s, 1H), 7.45 (dd, =1.7 Hz, J₂=8.5Hz, 1H), 6.76 (d, J=8.5 Hz, 1H), 4.54 (t, J=8.7 Hz, 2H), 3.21 (t, J=8.7Hz, 2H).

Intermediate E3N-Benzo[d][1,3]dioxol-5-yl)-2-chlorobenzo[d]thiazole-5-carboxamide

The title compound was prepared in analogy to Intermediate E2; LC-MS:t_(R)=0.86 min; [M+H]⁺=332.98; ¹H NMR (400 MHz, D₆-DMSO): δ 10.34 (s,1H), 8.56 (d, J=1.3 Hz, 1H), 8.27 (d, J=8.5 Hz, 1H), 8.06 (dd, =1.6 Hz,J₂=8.5 Hz, 1H), 7.48 (d, J=1.9 Hz, 1H), 7.23 (dd, J₁=2.0 Hz, J₂=8.4 Hz,1H), 6.93 (d, J=8.4 Hz, 1H), 6.03 (s, 2H).

Intermediate E42-Chloro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzo[d]thiazole-5-carboxamide

The title compound was prepared in analogy to Intermediate E2; LC-MS:t_(R)=0.87 min; [M+H]⁺=346.90; ¹H NMR (400 MHz, D₆-DMSO): δ 10.28 (s,1H), 8.56 (d, J=1.4 Hz, 1H), 8.26 (d, J=8.5 Hz, 1H), 8.06 (dd, J₁=1.6Hz, J₂=8.5 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.24 (dd, J₁=2.4 Hz, J₂=8.8Hz, 1H), 6.85 (d, J=8.7 Hz, 1H), 4.19-4.32 (m, 4H).

Example 1 2,3-Dihydro-benzofuran-5-carboxylic acid[2-(1,1-dioxo-1l6-thiomorpholin-4-yl)-benzooxazol-5-yl]-amide

To a solution of 2,3-dihydrobenzo[b]furan-5-carboxylic acid (18.5 mg,113 μmol) in DCM (2 mL) 1-chloro-N,N-2-trimethylpropenylamine (17 μL,124 μmop was added. The mixture was stirred at rt for 15 min beforeDIPEA (96 μL, 563 μmol) and 4-(5-aminobenzo[d]oxazol-2-yl)thiomorpholine1,1-dioxide (30.1 mg, 113 mmol) was added. Stirring was continued at rtfor 30 min. The mixture was diluted with DMF (2 mL) and separated usingprep. HPLC (column: XBridge Prep C18, 30×75 mm, 10 μm, gradient of MeCNin water containing 0.5% of 15 M aq. NH₄OH) to give the title compound(30 mg) as a white solid; LC-MS: t_(R)=0.73 min; [M+H]⁺=414.05; ¹H NMR(400 MHz, D₆-DMSO) δ: 10.03 (s, 1H), 7.88 (s, 1H), 7.77-7.82 (m, 2H),7.38-7.46 (m, 2H), 6.88 (d, J=8.4 Hz, 1H), 4.64 (t, J=8.8 Hz, 2H),4.04-4.11 (m, 4H), 3.32-3.39 (m, 4H), 3.26 (t, J=8.7 Hz, 2H).

Examples 2 to 41

The following Example compounds were prepared in analogy to Example 1starting from the appropriate Intermediates A2 to A39 and2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid,2,3-dihydrobenzofuran-5-carboxylic acid,4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid,benzo[d][1,3]dioxole-5-carboxylic acid, or chromane-6-carboxylic acid.

Exam- LC-MS ple Name t_(R) [min] [M + H]⁺ 22,3-Dihydro-benzofuran-5-carboxylic 0.78 364.26 acid(2-piperidin-1-yl-benzooxazol-5- yl)-amide 32,3-Dihydro-benzofuran-5-carboxylic 0.71 350.29 acid(2-pyrrolidin-1-yl-benzooxazol-5- yl)-amide 42,3-Dihydro-benzofuran-5-carboxylic 0.59 379.23 acid[2-(4-methyl-piperazin-1-yl)- benzooxazol-5-yl]-amide 52,3-Dihydro-benzofuran-5-carboxylic 0.76 366.25 acid(2-morpholin-4-yl-benzooxazol-5- yl)-amide 62,3-Dihydro-benzofuran-5-carboxylic 0.75 352.29 acid(2-diethylamino-benzooxazol-5- yl)-amide 72,3-Dihydro-benzofuran-5-carboxylic 0.86 400.20 acid[2-(4,4-difluoro-piperidin-1-yl)- benzooxazol-5-yl]-amide 82,3-Dihydro-benzofuran-5-carboxylic 0.82 372.10 acid[2-(3,3-difluoro-azetidin-1-yl)- benzooxazol-5-yl]-amide 92,3-Dihydro-benzofuran-5-carboxylic 0.93 386.04 acid[2-(3,3-difluoro-pyrrolidin-1-yl)- benzooxazol-5-yl]-amide 102,3-Dihydro-benzofuran-5-carboxylic 0.84 380.04 acid[2-(3-methoxy-pyrrolidin-1-yl)- benzooxazol-5-yl]-amide 112,3-Dihydro-benzofuran-5-carboxylic 0.89 394.09 acid[2-(4-methoxy-piperidin-1-yl)- benzooxazol-5-yl]-amide 122,3-Dihydro-benzofuran-5-carboxylic 0.78 366.04 acid[2-(3-hydroxy-3-methyl-azetidin- 1-yl)-benzooxazol-5-yl]-amide 132,3-Dihydro-benzofuran-5-carboxylic 0.60 381.08 acid{2-[(2-dimethylamino-ethyl)- methyl-amino]-benzooxazol-5-yl}-amide;compound with formic acid 14 2,3-Dihydro-benzofuran-5-carboxylic 0.78406.95 acid [2-(4-dimethylamino-piperidin-1-yl)-benzooxazol-5-yl]-amide; compound with formic acid 152,3-Dihydro-benzofuran-5-carboxylic 0.75 378.23 acid[2-(6-oxa-1-aza-spiro[3.3]hept-1- yl)-benzooxazol-5-yl]-amide 162,3-Dihydro-benzofuran-5-carboxylic 0.85 400.21 acid[2-(3,3-difluoro-piperidin-1-yl)- benzooxazol-5-yl]-amide 172,3-Dihydro-benzofuran-5-carboxylic 0.59 421.02 acid[2-(3-morpholin-4-yl-azetidin-1- yl)-benzooxazol-5-yl]-amide 182,3-Dihydro-benzofuran-5-carboxylic 0.78 380.20 acid{2-[methyl-(3-methyl-oxetan-3- yl)amino]-benzooxazol-5-yl}-amide 192,3-Dihydro-benzofuran-5-carboxylic 0.70 469.10 acid{2-[3-(1,1-dioxo-1I6- thiomorpholin-4-yl)-azetidin-1-yl]-benzooxazol-5-yl}-amide 20 2,3-Dihydro-benzofuran-5-carboxylic 0.61421.20 acid [2-(3-hydroxy-3-methyl- [1,3′]biazetidinyl-1′-yl)-benzooxazol-5-yl]-amide 21 2,3-Dihydro-benzofuran-5-carboxylic 0.74378.20 acid [2-(1-oxa-6-aza-spiro[3.3]hept-6-yl)-benzooxazol-5-yl]-amide 22 2,3-Dihydro-benzofuran-5-carboxylic 0.70392.20 acid [2-(2-oxa-6-aza-spiro[3.4]oct-6- yl)-benzooxazol-5-yl]-amide23 2,3-Dihydro-benzofuran-5-carboxylic 0.77 406.11 acid[2-(6-oxa-2-aza-spiro[3.5]non-2- yl)benzooxazol-5-yl]-amide 242,3-Dihydro-benzofuran-5-carboxylic 0.76 392.11 acid[2-(2-oxa-5-aza-spiro[3.4]oct-5- yl)-benzooxazol-5-yl]-amide 252,3-Dihydro-benzofuran-5-carboxylic 0.75 406.11 acid[2-(1-oxa-6-aza-spiro[3.5]non-6- yl)benzooxazol-5-yl]-amide 262,3-Dihydro-benzofuran-5-carboxylic 0.84 406.12 acid[2-(2-oxa-5-aza-spiro[3.5]non-5- yl)-benzooxazol-5-yl]-amide 272,3-Dihydro-benzofuran-5-carboxylic 0.76 406.09 acid[2-(1-oxa-7-aza-spiro[3.5]non-7- yl)-benzooxazol-5-yl]-amide 282,3-Dihydro-benzofuran-5-carboxylic 0.73 420.13 acid[2-(1-oxa-7-aza-spiro[3.5]non-7- yl)-benzooxazol-5-yl]-amide 292,3-Dihydro-benzofuran-5-carboxylic 0.80 420.12 acid[2-(1-oxa-8-aza-spiro[4.5]dec-8- yl)-benzooxazol-5-yl]-amide 302,3-Dihydro-benzofuran-5-carboxylic 0.76 406.11 acid[2-(7-oxa-2-aza-spiro[3.5]non-2- yl)benzooxazol-5-yl]-amide 312,3-Dihydro-benzofuran-5-carboxylic 0.78 392.11 acid[2-(5-oxa-2-aza-spiro[3.4]oct-2- yl)-benzooxazol-5-yl]-amide 322,3-Dihydro-benzofuran-5-carboxylic 0.58 435.15 acid{2-[3-(4-hydroxy-piperidin-1-yl)- azetidin-1-yl]-benzooxazol-5-yl}-amide33 2,3-Dihydro-benzofuran-5-carboxylic 0.61 419.14 acid[2-(6-methyl-2,6-diaza- spiro[3.5]non-2-yl)- benzooxazol-5-yl]-amide 342,3-Dihydro-benzofuran-5-carboxylic 0.82 406.12 acid[2-(5-oxa-2-aza-spiro[3.5]non-2- yl)-benzooxazol-5-yl]-amide 352,3-Dihydro-benzofuran-5-carboxylic 0.83 376.10 acid[2-(1-aza-spiro[3.3]hept-1-yl)- benzooxazol-5-yl]-amide 362,3-Dihydro-benzofuran-5-carboxylic 0.75 406.11 acid[2-(7-oxa-1-aza-spiro[3.5]non-1- yl)-benzooxazol-5-yl]-amide 371-{5-[(2,3-Dihydro-benzofuran-5- 0.88 436.11carbonyl)-aminol-benzooxazol-2-yl}- azetidine-3-carboxylic acidtert-butyl ester 38 2,3-Dihydro-benzofuran-5-carboxylic 0.66 364.15 acid[2-(2-oxo-pyrrolidin-1-yl)- benzooxazol-5-yl]-amide 392,3-Dihydro-benzo[1,4]dioxine- 0.73 429.90 6-carboxylic acid[2-(1,1-dioxo- thiomorpholin-4-yl)- benzooxazol-5-yl]-amide 40Chroman-6-carboxylic acid 0.77 427.97 [2-(1,1-dioxo-thiomorpholin-4-yl)-benzooxazol- 5-yl]-amide 41 4-Methyl-3,4-dihydro- 0.75 442.942H-benzo[1,4]oxazine- 6-carboxylic acid [2-(1,1-dioxo-thiomorpholin-4-yl)- benzooxazol-5-yl]-amide

Example 3: ¹H NMR (400 MHz, D₆-DMSO) δ: 10.01 (s, 1H), 7.83 (s, 1H),7.74 (d, J=8.8 Hz, 1H), 7.64 (s, 1H), 7.27-7.33 (m, 2H), 6.85 (d, J=8.1Hz, 1H), 4.60 (t, J=8.8 Hz, 2H), 3.50-3.55 (m, 4H), 3.23 (t, J=8.3 Hz,2H), 1.91-1.99 (m, 4H).

Example 5: ¹H NMR (400 MHz, D₆-DMSO) δ: 10.04 (s, 1H), 7.84 (s, 1H),7.75 (d, J=8.2 Hz, 1H), 7.71 (s, 1H), 7.35 (s, 2H), 6.85 (dd, J₁=2.2 Hz,J_(z)=8.3 Hz, 1H), 4.56-4.65 (m, 2H), 3.51-3.69 (m, 8H), 3.19-3.27 (m,2H).

Example 6: ¹H NMR (400 MHz, D₆-DMSO) δ: 10.01 (s, 1H), 7.83 (s, 1H),7.75 (d, J=8.6 Hz, 1H), 7.63 (s, 1H), 7.23-7.33 (m, 2H), 6.85 (d, J=8.3Hz, 1H), 4.60 (t, J=8.7 Hz, 2H), 3.50 (q, J=6.7 Hz, 4H), 3.23 (t, J=8.6Hz, 2H), 1.18 (t, J=6.9 Hz, 6H).

Example 15: ¹H NMR (400 MHz, DMSO) δ: 10.04 (s, 1H), 7.89 (s, 1H),7.78-7.83 (m, 2H), 7.43 (s, 2H), 6.89 (d, J=8.4 Hz, 1H), 5.22 (d, J=7.5Hz, 2H), 4.61-4.69 (m, 4H), 4.02 (t, J=7.3 Hz, 2H), 3.27 (t, J=8.7 Hz,2H), 2.73 (t, J=7.2 Hz, 2H).

Example 23: ¹H NMR (400 MHz, DMSO) δ: 10.02 (s, 1H), 7.89 (s, 1H), 7.80(d, J=8.3 Hz, 1H), 7.76 (d, J=1.2 Hz, 1H), 7.34-7.43 (m, 2H), 6.89 (d,J=8.4 Hz, 1H), 4.65 (t, J=8.7 Hz, 2H), 3.87-3.95 (m, 4H), 3.68 (s, 2H),3.51-3.56 (m, 2H), 3.27 (t, J=8.6 Hz, 2H), 1.84-1.91 (m, 2H), 1.50-1.58(m, 2H).

Example 26: ¹H NMR (400 MHz, DMSO) δ: 10.05 (s, 1H), 7.88 (s, 1H),7.76-7.81 (m, 2H), 7.40 (s, 2H), 6.89 (d, J=8.4 Hz, 1H), 4.79-4.84 (m,2H), 4.64 (t, J=8.7 Hz, 2H), 4.43-4.48 (m, 2H), 3.27 (t, J=8.7 Hz, 2H),2.02-2.09 (m, 2H), 1.69-1.77 (m, 2H), 1.39-1.47 (m, 2H).

Example 30: ¹H NMR (400 MHz, DMSO) δ: 10.01 (s, 1H), 7.89 (s, 1H), 7.80(d, J=8.4 Hz, 1H), 7.76 (d, J=1.2 Hz), 7.34-7.43 (m, 2H), 6.89 (d, J=8.4Hz, 1H), 4.65 (t, J=8.7 Hz, 2H), 3.98 (s, 4H), 3.53-3.60 (m, 2H), 3.27(t, J=8.7 Hz, 2H), 1.76-1.84 (m, 4H).

Example 34: ¹H NMR (400 MHz, CDCl₃) δ: 7.82 (s, 1H), 7.80 (s, 1H), 7.68(dd, J₁=1.4 Hz, J₂=8.3 Hz, 1H), 7.53 (d, J=1.9 Hz, 1H), 7.43 (dd, J₁=2.0Hz, J₂=8.6 Hz, 1H), 7.25 (d, J=8.6 Hz, 1H), 6.85 (d, J=8.3 Hz, 1H), 4.68(t, J=8.8 Hz, 2H), 4.21 (d, J=8.7 Hz, 2H), 4.11 (d, J=8.7 Hz, 2H),3.69-3.73 (m, 2H), 3.29 (t, J=8.7 Hz, 2H), 1.86-1.92 (m, 2H), 1.68-1.75(m, 2H), 1.57-1.64 (m, 2H).

Example 39: ¹H NMR (400 MHz, DMSO) δ: 10.06 (s, 1H), 7.77 (s, 1H),7.47-7.53 (m, 2H), 7.40 (s, 2H), 6.98 (d, J=8.3 Hz, 1H), 4.26-4.35 (m,4H), 4.03-4.11 (m, 4H), 3.30-3.37 (m, 4H).

Example 41: ¹H NMR (400 MHz, DMSO) δ: 9.99 (s, 1H), 7.77 (s, 1H), 7.39(s, 2H), 7.23-7.29 (m, 2H), 6.77 (d, J=8.8 Hz, 1H), 4.26-4.33 (m, 2H),4.03-4.11 (m, 4H), 3.30-3.37 (m, 4H), 3.24-3.30 (m, 2H), 2.90 (s, 3H).

Example 371-{5-[(2,3-Dihydro-benzofuran-5-carbonyl)-amino]-benzooxazol-2-yl}-azetidine-3-carboxylicAcid tert-butyl Ester

To a solution of 2,3-dihydrobenzofuran-5-carboxylic acid (10 mg, 63μmol) and HBTU (24 mg, 63 μmol) in DMF (1 mL) DIPEA (33 μL, 190 μmol)was added. The mixtures were stirred at rt for 30 min before bytert-butyl 1-(5-aminobenzo[d]oxazol-2-yl)azetidine-3-carboxylate (18 mg,63 μmol) was added. Stirring was continued at 55° C. for 16 h. Themixture was separated by prep. HPLC to give1-{5-[(2,3-dihydro-benzofuran-5-carbonyl)-amino]-benzooxazol-2-yl}-azetidine-3-carboxylicacid tert-butyl ester (4 mg) as a colourless resin; LC-MS: t_(R)=0.88min; [M+H]⁺=436.11.

Example 42(R)—N-(2-(3-hydroxypiperidin-1-yl)benzo[d]oxazol-5-yl)-2,3-dihydrobenzofuran-5-carboxamide

To a mixture ofN-(2-mercaptobenzo[d]oxazol-5-yl)-2,3-dihydrobenzofuran-5-carboxamide(Intermediate B1) (20 mg, 64 μmol) in DCM (1 mL) and SOCl₂ (0.1 mL) DMF(20 μL) was added. The suspension was stirred at rt for 1 h before thesolvent was removed in vacuo to give crudeN-(2-chlorobenzo[d]oxazol-5-yl)-2,3-dihydrobenzofuran-5-carboxamid;LC-MS: t_(R)=0.85 min; [M+H]⁺=314.96. To this material a solution of(R)-piperidin-3-ol (7.8 mg, 77 μmol) in DMF (0.8 mL) and K₂CO₃ (27 mg,192 μmol) was added. The mixture was stirred at 70° C. for 16 h beforeit was cooled to rt and separated by prep. HPLC to give the titlecompound (7 mg) as a colourless resin; LC-MS: t_(R)=0.68 min;[M+H]⁺=380.15; ¹H NMR (400 MHz, DMSO) δ: 9.99 (s, 1H), 7.86 (s, 1H),7.77 (d, J=8.3 Hz, 1H), 7.69 (s, 1H), 7.30-7.36 (m, 2H), 6.87 (d, J=8.3Hz, 1H), 5.06 (d, J=4.0 Hz, 1H), 4.63 (t, J=8.6 Hz, 2H), 3.88 (dd,J₁=3.4 Hz, J₂=13.0 Hz, 1H), 3.73-3.79 (m, 1H), 3.59-3.65 (m, 1H),3.29-3.36 (m, 1H), 3.25 (t, J=8.8 Hz, 2H), 3.14 (dd, J, =8.1 Hz, J₂=12.5Hz, 1H), 1.79-1.90 (m, 2H), 1.37-1.54 (m, 2H).

Examples 43 to 74

The following Example compounds were prepared in analogy to Example 42starting from Intermediate B1 and the appropriate amines.

Exam- LC-MS ple Name t_(R) [min] [M + H]⁺ 432,3-Dihydro-benzofuran-5-carboxylic 0.74 380.08 acid[2-((S)-3-hydroxy-piperidin-1-yl)- benzooxazol-5-yl]-amide 442,3-Dihydro-benzofuran-5-carboxylic 0.94 394.05 acid[2-(3-isopropoxy-azetidin-1-yl)- benzooxazol-5-yl]-amide 452,3-Dihydro-benzofuran-5-carboxylic 0.63 366.20 acid[2-((R)-3-hydroxy-pyrrolidin-1-yl)- benzooxazol-5-yl]-amide 462,3-Dihydro-benzofuran-5-carboxylic 0.71 365.76 acid[2-((S)-3-hydroxy-pyrrolidin-1-yl)- benzooxazol-5-yl]-amide 472,3-Dihydro-benzofuran-5-carboxylic 0.70 352.03 acid[2-(3-hydroxy-azetidin-1-yl)- benzooxazol-5-yl]-amide 482,3-Dihydro-benzofuran-5-carboxylic 0.73 380.02 acid[2-(4-hydroxy-piperidin-1-yl)- benzooxazol-5-yl]amide 492,3-Dihydro-benzofuran-5-carboxylic 1.02 411.94 acid[2-(3-phenyl-azetidin-1-yl)- benzooxazol-5-yl]-amide 502,3-Dihydro-benzofuran-5-carboxylic 0.81 405.99 acid[2-(2-oxa-7-aza-spiro[3.5]non-7-yl)- benzooxazol-5-yl]-amide 512,3-Dihydro-benzofuran-5-carboxylic 1.02 408.02 acid[2-(2-ethoxymethyl-pyrrolidin-1-yl)- benzooxazol-5-yl]-amide 522,3-Dihydro-benzofuran-5-carboxylic 0.82 397.73 acid{2-[(3-fluoro-oxetan-3-ylmethyl)- methyl-amino]-benzooxazol-5-yl}-amide53 2,3-Dihydro-benzofuran-5-carboxylic 0.59 421.18 acid[2-(4-oxetan-3-yl-piperazin-1-yl)- benzooxazol-5-yl]amide 542,3-Dihydro-benzofuran-5-carboxylic 0.74 448.93 acid{2-[methyl-(1-oxetan-3-yl-piperidin-4-yl)-amino]-benzooxazol-5-yl}-amide 552,3-Dihydro-benzofuran-5-carboxylic 0.78 405.94 acid[2-(2-oxa-6-aza-spiro[3.5]non-6-yl)- benzooxazol-5-yl]-amide 562,3-Dihydro-benzofuran-5-carboxylic 0.77 379.94 acid[2-(methyl-oxetan-3-ylmethyl- amino)-benzooxazol-5-yl]-amide 572,3-Dihydro-benzofuran-5-carboxylic 0.77 365.71 acid[2-(methyl-oxetan-3-yl-amino)- benzooxazol-5-yl]-amide 582,3-Dihydro-benzofuran-5-carboxylic 0.95 393.95 acid[2-(2-methoxymethyl-pyrrolidin-1- yl)-benzooxazol-5-yl]-amide 592,3-Dihydro-benzofuran-5-carboxylic 0.87 393.98 acid[2-(3-methoxy-piperidin-1-yl)- benzooxazol-5-yl]-amide 602,3-Dihydro-benzofuran-5-carboxylic 0.86 407.04 acid[2-(3-dimethylaminomethyl- pyrrolidin-1-yl)-benzooxazol-5-yl]-amide 612,3-Dihydro-benzofuran-5-carboxylic 0.66 407.24 acid[2-(2-dimethylaminomethyl- pyrrolidin-1-yl)-benzooxazol-5-yl]-amide 62rac-2,3-Dihydro-benzofuran-5-carboxylic 0.96 412.01 acid[2-(2-phenyl-azetidin-1-yl)- benzooxazol-5-yl]-amide 632,3-Dihydro-benzofuran-5-carboxylic 0.82 391.99 acid[2-(cyclopropyl-oxetan-3-yl-amino)- benzooxazol-5-yl]-amide 642,3-Dihydro-benzofuran-5-carboxylic 0.78 405.02 acid[2-(3-pyrrolidin-1-yl-azetidin-1-yl)- benzooxazol-5-yl]-amide 652,3-Dihydro-benzofuran-5-carboxylic 0.76 393.80 acid{2-[3-(1-hydroxy-1-methyl-ethyl)- azetidin-1-yl]-benzooxazol-5-yl}-amide66 2,3-Dihydro-benzofuran-5-carboxylic 0.76 392.93 acid[2-(3-dimethylaminomethyl- azetidin-1-yl)-benzooxazol-5-yl]-amide 672,3-Dihydro-benzofuran-5-carboxylic 0.62 419.15 acid[2-(7-methyl-1,7-diaza- spiro[3.5]non-1-yl)- benzooxazol-5-yl]-amide 682,3-Dihydro-benzofuran-5-carboxylic 0.77 419.03 acid[2-(7-methyl-2,7-diaza- spiro[3.5]non-2-yl)- benzooxazol-5-yl]-amide 692,3-Dihydro-benzofuran-5-carboxylic 0.78 379.01 acid[2-(3-dimethylamino-azetidin-1-yl)- benzooxazol-5-yl]-amide 702,3-Dihydro-benzofuran-5-carboxylic 0.76 425.87 acid[2-(2,2-dioxo-2I6-thia-6-aza- spiro[3.3]hept-6-yl)-benzooxazol-5-yl]-amide 71 2,3-Dihydro-benzofuran-5-carboxylic 0.80391.99 acid [2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)- benzooxazol-5-yl]-amide72 2,3-Dihydro-benzofuran-5-carboxylic 0.75 425.90 acid[2-(1,1-dioxo-1I6-thia-6-aza- spiro[3.3]hept-6-yl)-benzooxazol-5-yl]-amide 73 2,3-Dihydro-benzofuran-5-carboxylic 0.81393.02 acid [2-(3-dimethylamino-3-methyl-azetidin-1-yl)-benzooxazol-5-yl]-amide 742,3-Dihydro-benzofuran-5-carboxylic 0.77 391.95 acid[2-(6-oxa-2-aza-spiro[3.4]oct-2-yl)- benzooxazol-5-yl]-amide

Example 44: ¹H NMR (400 MHz, DMSO) δ: 10.02 (s, 1H), 7.86 (s, 1H), 7.77(dd, J₁=1.2 Hz, J₂=8.3 Hz, 1H), 7.74 (d, J=1.2 Hz, 1H), 7.38 (dd, =1.7Hz, J₂=8.8 Hz, 1H), 7.35 (d, J=8.6 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H), 4.63(t, J=8.7 Hz, 2H), 4.52-4.58 (m, 1H), 4.38-4.44 (m, 2H), 3.99 (dd,J₁=4.6 Hz, J₂=9.0 Hz, 2H), 3.65 (hept, J=6.6 Hz, 1H), 3.25 (t, J=8.6 Hz,2H), 1.11 (d, J=6.1 Hz, 6H).

Example 47: ¹H NMR (400 MHz, DMSO) δ: 10.01 (s, 1H), 7.86 (s, 1H), 7.77(d, J=8.3 Hz, 1H), 7.73 (d, J=0.7 Hz, 1H), 7.32-7.40 (m, 2H), 6.87 (d,J=8.3 Hz, 1H), 5.93 (d, J=6.8 Hz, 1H), 4.59-4.66 (m, 3H), 4.38 (t, J=7.8Hz, 2H), 3.95 (dd, =4.6 Hz, J₂=8.6 Hz, 2H), 3.25 (t, J=8.6 Hz, 2H).

Example 50: ¹H NMR (400 MHz, DMSO) δ: 10.00 (s, 1H), 7.86 (s, 1H), 7.77(dd, J₁=0.7 Hz, J₂=8.3 Hz, 1H), 7.70 (s, 1H), 7.30-7.37 (m, 2H), 6.87(d, J=8.3 Hz, 1H), 4.62 (t, J=8.8 Hz, 2H), 4.36 (s, 4H), 3.52-3.57 (m,2H), 3.25 (t, J=8.8 Hz, 2H), 1.85-1.91 (m, 4H).

Example 57: ¹H NMR (400 MHz, DMSO) δ: 10.02 (s, 1H), 7.86 (s, 1H), 7.77(d, J=8.6 Hz, 1H), 7.73 (s, 1H), 7.30-7.40 (m, 2H), 6.87 (d, J=8.3 Hz,1H), 5.25 (quint, J=6.8 Hz, 1H), 4.76-4.83 (m, 4H), 4.62 (t, J=8.6 Hz,2H), 3.25 (t, J=8.6 Hz, 2H), 3.23 (s, 3H).

Example 70: ¹H NMR (400 MHz, DMSO) δ: 10.03 (s, 1H), 7.87 (s, 1H),7.76-7.80 (m, 2H), 7.36-7.44 (m, 2H), 6.87 (d, J=8.3 Hz, 1H), 4.63 (t,J=8.6 Hz, 2H), 4.54 (s, 4H), 4.45 (s, 4H), 3.25 (t, J=8.8 Hz, 2H).

Example 71: ¹H NMR (400 MHz, DMSO) δ: 10.01 (s, 1H), 7.87 (s, 1H), 7.78(dd, J₁=1.0 Hz, J₂=8.3 Hz, 1H), 7.74 (s, 1H), 7.33-7.41 (m, 2H), 6.87(d, J=8.4 Hz, 1H), 4.63 (t, J=8.7 Hz, 2H), 3.98-4.12 (m, 4H), 3.77-3.88(m, 2H), 3.26 (t, J=9.0 Hz, 2H), 2.54-2.64 (m, 2H), 2.09-2.20 (m, 2H).

Example 72: ¹H NMR (400 MHz, DMSO) δ: 10.06 (s, 1H), 7.87 (s, 1H), 7.85(s, 1H), 7.78 (d, J=8.3 Hz), 7.38-7.46 (m, 2H), 6.88 (d, J=8.4 Hz, 1H),5.03-5.11 (m, 2H), 4.63 (t, J=8.6 Hz, 2H), 4.44-4.52 (m, 2H), 4.13-4.19(m, 2H), 3.26 (t, J=8.6 Hz, 2H), 2.89 (t, J=6.8 Hz, 2H).

Example 75 2-(4-Methyl-piperazin-1-yl)-benzooxazole-5-carboxylic acid(2,3-dihydro-benzofuran-5-yl)-amide

To a solution of 2-(4-methylpiperazin-1-yl)benzo[d]oxazole-5-carboxylicacid (45 mg, 172 μmol) and 5-amino-2,3-dihydrobenzofuran (47 mg, 344μmol) in DCM (2 mL) and pyridine (0.14 mL) POCl₃ (17 μL, 189 μmol) wasadded. The mixture was stirred at rt for 30 min gefore it wasconcentrated. The residue was dissolved in acetonitrile (1 mL) andseparated by prep. HPLC to give the title compound (35 mg) as a beigesolid; LC-MS: t_(R)=0.57 min; [M+H]⁺=379.19; ¹H NMR (400 MHz, CDCl₃) δ:7.81 (s, 1H), 7.75 (s, 1H), 7.67 (s, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.33(d, J=8.3 Hz, 1H), 7.16 (dd, J₁=0.7 Hz, J₂=8.2 Hz, 1H), 6.78 (d, J=8.5Hz, 1H), 4.61 (t, J=8.7 Hz, 2H), 3.76-3.85 (m, 4H), 3.25 (t, J=8.7 Hz,2H), 2.56-2.66 (m, 4H), 2.41 (s, 3H).

Examples 76 to 80

The following Example compounds were prepared in analogy to Example 75starting from Intermediates C2 to C6 and 5-amino-2,3-dihydrobenzofuran.

Exam- LC-MS ple Name t_(R) [min] [M + H]⁺ 762-Piperidin-1-yl-benzooxazole-5- 0.84 364.01 carboxylic acid(2,3-dihydro-benzofuran-5- yl)-amide 77 2-Morpholin-4-yl-benzooxazole-5-0.76 366.14 carboxylic acid (2,3-dihydro-benzofuran- 5-yl)-amide 782-Diethylamino-benzooxazole-5- 0.81 352.05 carboxylic acid(2,3-dihydro-benzofuran-5- yl)-amide 792-Pyrrolidin-1-yl-benzooxazole-5- 0.76 350.02 carboxylic acid(2,3-dihydro-benzofuran- 5-yl)-amide 802-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)- 0.75 377.98benzooxazole-5-carboxylic acid (2,3- dihydro-benzofuran-5-yl)-amide

Example 76: ¹H NMR (400 MHz, CDCl₃) δ: 7.81 (s, 2H), 7.67 (s, 1H), 7.63(d, J=8.3 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.17 (dd, =1.5 Hz, J₂=8.3 Hz,1H), 6.78 (d, J=8.5 Hz, 1H), 4.61 (t, J=8.7 Hz, 2H), 3.69-3.77 (m, 4H),3.26 (t, J=8.7 Hz, 2H), 1.70-1.78 (m, 6H).

Example 77: ¹H NMR (400 MHz, CDCl₃) δ: 7.84 (s, 1H), 7.75 (s, 1H),7.63-7.69 (m, 2H), 7.36 (d, J=8.3 Hz, 1H), 7.16 (dd, =1.1 Hz, J₂=8.4 Hz,1H), 6.79 (d, J=8.4 Hz, 1H), 4.61 (t, J=8.7 Hz, 2H), 3.84-3.89 (m, 4H),3.73-3.79 (m, 4H), 3.26 (t, J=8.7 Hz, 2H).

Example 78: ¹H NMR (400 MHz, CDCl₃) δ: 7.80 (d, J=0.8 Hz, 1H), 7.75 (s,1H), 7.68 (s, 1H), 7.60 (dd, J₁=1.2 Hz, J₂=8.3 Hz, 1H), 7.33 (d, J=8.3Hz, 1H), 7.16 (dd, J₁=1.5 Hz, J₂=8.3 Hz), 6.78 (d, J=8.5 Hz, 1H), 4.61(t, J=8.7 Hz, 2H), 3.64 (q, J=7.1 Hz, 4H), 3.26 (t, J=8.6 Hz, 2H), 1.33(t, J=7.1 Hz, 6H).

Example 79: ¹H NMR (400 MHz, CDCl₃) δ: 7.82 (d, J=0.7 Hz, 1H), 7.80 (s,1H), 7.68 (s, 1H), 7.61 (dd, J₁=1.4 Hz, J₂=8.3 Hz, 1H), 7.34 (d, J=8.3Hz, 1H), 7.17 (dd, J₁=1.5 Hz, J₂=8.5 Hz, 1H), 6.78 (d, J=8.5 Hz, 1H),4.61 (t, J=8.7 Hz, 2H), 3.67-3.74 (m, 4H), 3.26 (t, J=8.6 Hz, 2H),2.03-2.13 (m, 4H).

Example 80: ¹H NMR (400 MHz, CDCl₃) δ: 7.90 (s, 1H), 7.79 (s br, 1H),7.66-7.71 (m, 2H), 7.43 (d, J=8.3 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 6.79(d, J=8.5 Hz, 1H), 5.43 (d, J=7.5 Hz, 2H), 4.79 (d, J=7.5 Hz, 2H), 4.61(t, J=8.7 Hz, 2H), 4.15 (t, J=7.3 Hz, 2H), 3.26 (t, J=8.6 Hz, 2H), 2.80(t, J=7.2 Hz, 2H).

Example 81 2,3-Dihydro-benzofuran-5-carboxylic acid(2-piperidin-1-yl-benzothiazol-5-yl)-amide

To a solution of 2-(piperidin-1-yl)benzo[d]thiazol-5-amine (53 mg, 226μmol) and 2,3-dihydrobenzo[b]furan-5-carboxylic acid (37 mg, 226 μmol)in MeCN (2 mL) pyridine (0.18 mL) followed by POCI₃ (0.23 mL, 248 μmopwas added. The mixture was stirred at rt for 15 in before it was dilutedwith water (0.25 mL) and then concentrated. The residue was dissolved inDMF (1.5 mL) and formic acid (0.1 mL) and separated by prep. HPLC togive the title compound (31 mg) as a solid; LC-MS: t_(R)=0.76 min;[M+H]⁺=380.25; ¹H NMR (400 MHz, CDCl₃) δ: 7.80 (s, 2H), 7.66-7.71 (m,2H), 7.56 (s, 2H), 6.86 (d, J=8.3 Hz, 1H), 4.68 (t, J=8.8 Hz, 2H),3.60-3.67 (m, 4H), 3.29 (t, J=8.7 Hz, 2H), 1.68-1.78 (m, 6H).

Examples 82 to 97

The following Example compounds were prepared in analogy to Example 81starting from Intermediates D2 to D17 and2,3-dihydrobenzo[b]furan-5-carboxylic acid.

Exam- LC-MS ple Name t_(R) [min] [M + H]⁺ 822,3-Dihydro-benzofuran-5-carboxylic 0.76 382.23 acid(2-morpholin-4-yl-benzothiazol-5- yl)-amide 832,3-Dihydro-benzofuran-5-carboxylic 0.62 395.22 acid[2-(4-methyl-piperazin-1-yl)- benzothiazol-5-yl]amide 842,3-Dihydro-benzofuran-5-carboxylic 0.69 366.17 acid(2-pyrrolidin-1-yl-benzothiazol-5- yl)-amide 852,3-Dihydro-benzofuran-5-carboxylic 0.73 367.98 acid(2-diethylamino-benzothiazol-5- yl)-amide 862,3-Dihydro-benzofuran-5-carboxylic 0.66 344.01 acid(2-dimethylamino-benzothiazol- 5-yl)-amide 872,3-Dihydro-benzofuran-5-carboxylic 0.85 388.11 acid[2-(3,3-difluoro-azetidin-1-yl)- benzothiazol-5-yl]-amide 882,3-Dihydro-benzofuran-5-carboxylic 0.84 401.96 acid[2-(3,3-difluoro-pyrrolidin-1-yl)- benzothiazol-5-yl]-amide 892,3-Dihydro-benzofuran-5-carboxylic 0.89 416.07 acid[2-(3,3-difluoro-piperidin-1-yl)- benzothiazol-5-yl]-amide 902,3-Dihydro-benzofuran-5-carboxylic 0.75 394.12 acid[2-(6-oxa-1-aza-spiro[3.3]hept-1- yl)-benzothiazol-5-yl]-amide 912,3-Dihydro-benzofuran-5-carboxylic 0.69 394.12 acid[2-(2-oxa-6-aza-spiro[3.3]hept-6- yl)-benzothiazol-5-yl]-amide 922,3-Dihydro-benzofuran-5-carboxylic 0.78 430.01 acid[2-(1,1-dioxo-1I6-thiomorpholin- 4-yl)-benzothiazol-5-yl]-amide 932,3-Dihydro-benzofuran-5-carboxylic 0.64 397.16 acid{2-[(2-dimethylamino-ethyl)- methyl-amino]-benzothiazol-5-yl}-amide 942,3-Dihydro-benzofuran-5-carboxylic 0.70 396.14 acid[2-(3-methoxy-pyrrolidin-1-yl)- benzothiazol-5-yl]-amide 952,3-Dihydro-benzofuran-5-carboxylic 0.77 410.12 acid[2-(4-methoxy-piperidin-1-yl)- benzothiazol-5-yl]-amide 962,3-Dihydro-benzofuran-5-carboxylic 0.67 382.14 acid[2-(3-hydroxy-3-methyl-azetidin- 1-yl)-benzothiazol-5-yl]-amide 972,3-Dihydro-benzofuran-5-carboxylic 0.62 423.13 acid[2-(4-dimethylamino-piperidin-1- yl)-benzothiazol-5-yl]-amide

Example 82: ¹H NMR (400 MHz, CDCl₃) δ: 7.80 (s, 2H), 7.76 (d, J=1.7 Hz,1H), 7.69 (dd, =1.8 Hz, J₂=8.3 Hz, 1H), 7.58 (m, 2H), 6.86 (d, J=8.3 Hz,1H), 4.69 (t, J=8.8 Hz, 2H), 3.86 (m, 4H), 3.66 (m, 4H), 3.30 (t, J=8.8Hz, 2H).

Example 83: ¹H NMR (400 MHz, D₆-DMSO) δ: 10.06 (s, 1H), 7.98 (d, J=1.9Hz, 1H), 7.89 (s, 1H), 7.80 (dd, J₁=1.8 Hz, J₂=8.4 Hz, 1H), 7.69 (d,J=8.5 Hz, 1H), 7.48 (dd, J₁=2.0 Hz, J₂=8.6 Hz, 1H), 6.89 (d, J=8.4 Hz,1H), 4.64 (t, J=8.8 Hz, 2H), 3.56-3.61 (m, 4H), 3.27 (t, J=8.7 Hz, 2H),2.49-2.53 (m, 4H), 2.30 (s, 3H).

Example 87: ¹H NMR (400 MHz, CDCl₃) δ: 7.84 (s, 1H), 7.81 (s, 2H), 7.69(dd, J₁=1.8 Hz, J₂=8.8 Hz), 7.59-7.65 (m, 2H), 6.87 (d, J=8.3 Hz, 1H),4.70 (t, J=8.8 Hz, 2H), 4.59 (t, J=11.7 Hz, 4H), 3.30 (t, J=8.7 Hz, 2H).

Example 90: ¹H NMR (400 MHz, D₆-DMSO) δ: 10.09 (s, 1H), 8.07 (s, 1H),7.90 (s, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.50 (d,J=8.6 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 5.34 (d, J=7.2 Hz, 2H), 4.59-4.74(m, 4H), 3.90-4.02 (m, 2H), 3.29 (t, J=8.7 Hz, 2H), 2.68-2.79 (m, 2H).

Example 92: ¹H NMR (400 MHz, D₆-DMSO) δ: 10.08 (s, 1H), 8.04 (d, J=1.9Hz, 1H), 7.89 (s, 1H), 7.80 (dd, =1.6 Hz, J₂=8.4 Hz, 1H), 7.74 (d, J=8.6Hz, 1H), 7.51 (dd, =1.9 Hz, J₂=8.6 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 4.64(t, J=8.8 Hz, 2H), 4.04-4.09 (m, 4H), 3.31-3.34 (m, 4H), 3.27 (t, J=8.8Hz, 2H).

Example 96: ¹H NMR (400 MHz, D₆-DMSO) δ: 10.05 (s, 1H), 7.96 (d, J=1.9Hz, 1H), 7.88 (s, 1H), 7.79 (dd, =1.4 Hz, J₂=8.4 Hz, 1H), 7.68 (d, J=8.6Hz, 1H), 7.48 (dd, =1.9 Hz, J₂=8.6 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 5.85(s br, 1H), 4.64 (t, J=8.8 Hz, 2H), 3.95-4.04 (m, 4H), 3.27 (t, J=8.7Hz, 2H), 1.47 (s, 3H).

Example 98(S)—N-(2-(3-hydroxypyrrolidin-1-yl)benzo[d]thiazol-5-yl)-2,3-dihydrobenzofuran-5-carboxamide

To a solution of (S)-pyrrolidin-3-ol (8 mg, 91 μmol) and Et₃N (51 μL,362 μmol) in THF (0.6 mL)N-(2-chlorobenzo[d]thiazol-5-yl)-2,3-dihydrobenzofuran-5-carboxamide (30mg, 72.5 μmol) was added and the mixture was stirred at 65° C. for 16 h.The mixture was concentrated, dissolved in DMSO (0.6 mL) and separatedby prep. HPLC to give the title compound (17 mg) as a white solid;LC-MS: t_(R)=0.80 min; [M+H]⁺=382.00; ¹H NMR (400 MHz, DMSO) δ: 10.06(s, 1H), 7.89 (s, 1H), 7.85 (s, H), 7.76 (d, J=8.3 Hz, 1H), 7.64 (d,J=8.6 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 5.28 (d,J=3.2 Hz, 1H), 4.61 (t, J=8.6 Hz, 2H), 4.40-4.46 (m, 1H), 3.66-3.82 (m,4H), 3.24 (t, J=8.6 Hz, 2H), 2.04-2.17 (m, 1H), 1.89-2.00 (m, 1H).

Examples 99 to 117

The following Example compounds were prepared in analogy to Example 98starting from Intermediate E1 and the appropriate amines.

Exam- LC-MS ple Name t_(R) [min] [M + H]⁺ 992,3-Dihydro-benzofuran-5-carboxylic 0.91 421.68 acid[2-(2-oxa-7-aza-spiro[3.5]non- 7-yl)-benzothiazol-5-yl]-amide 1002,3-Dihydro-benzofuran-5-carboxylic 0.87 465.05 acid{2-[methyl-(1-oxetan-3-yl- piperidin-4-yl)-amino]-benzothiazol-5-yl}-amide 101 2,3-Dihydro-benzofuran-5-carboxylic 0.93421.70 acid [2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzothiazol-5-yl]-amide 102 2,3-Dihydro-benzofuran-5-carboxylic0.84 437.02 acid [2-(4-oxetan-3-yl-piperazin-1-yl)-benzothiazol-5-yl]-amide 103 2,3-Dihydro-benzofuran-5-carboxylic0.87 382.01 acid [2-(methyl-oxetan-3-yl-amino)- benzothiazol-5-yl]-amide104 2,3-Dihydro-benzofuran-5-carboxylic 0.88 394.01 acid[2-(1-oxa-6-aza-spiro[3.3]hept- 6-yl)-benzothiazol-5-yl]-amide 1052,3-Dihydro-benzofuran-5-carboxylic 0.96 422.95 acid[2-(3-dimethylaminomethyl- pyrrolidin-1-yl)-benzothiazol-5-yl]-amide 1062,3-Dihydro-benzofuran-5-carboxylic 1.01 410.05 acid[2-(3-isopropoxy-azetidin-1-yl)- benzothiazol-5-yl]-amide 1072,3-Dihydro-benzofuran-5-carboxylic 1.07 424.05 acid[2-(2-ethoxymethyl-pyrrolidin-1- yl)-benzothiazol-5-yl]-amide 1082,3-Dihydro-benzofuran-5-carboxylic 0.98 410.02 acid[2-(3-methoxy-piperidin-1-yl)- benzothiazol-5-yl]-amide 1092,3-Dihydro-benzofuran-5-carboxylic 0.79 367.97 acid[2-(3-hydroxy-azetidin-1-yl)- benzothiazol-5-yl]-amide 1102,3-Dihydro-benzofuran-5-carboxylic 0.83 395.99 acid[2-(4-hydroxy-piperidin-1-yl)- benzothiazol-5-yl]-amide 111rac-2,3-Dihydro-benzofuran-5-carboxylic 1.10 428.00 acid[2-(2-phenyl-azetidin-1- yl)-benzothiazol-5-yl]-amide 1122,3-Dihydro-benzofuran-5-carboxylic 0.81 381.98 acid[2-((R)-3-hydroxy-pyrrolidin-1- yl)-benzothiazol-5-yl]-amide 1132,3-Dihydro-benzofuran-5-carboxylic 1.00 410.01 acid[2-(2-methoxymethyl-pyrrolidin- 1-yl)-benzothiazol-5-yl]-amide 1142,3-Dihydro-benzofuran-5-carboxylic 0.85 396.00 acid[2-((S)-3-hydroxy-piperidin-1- yl)-benzothiazol-5-yl]-amide 1152,3-Dihydro-benzofuran-5-carboxylic 0.87 408.02 acid[2-(2-oxa-6-aza-spiro[3.4]oct-6- yl)-benzothiazol-5-yl]-amide 1162,3-Dihydro-benzofuran-5-carboxylic 0.85 395.99 acid[2-((R)-3-hydroxy-piperidin-1- yl)-benzothiazol-5-yl]-amide 1172,3-Dihydro-benzofuran-5-carboxylic 1.05 422.94 acid[2-(2-dimethylaminomethyl- pyrrolidin-1-yl)-benzothiazol-5-yl]-amide

Example 101: ¹H NMR (400 MHz, D₆-DMSO) δ: 10.08 (s, 1H), 7.90 (s, 1H),7.85 (s, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.42 (dd,J₁=1.1 Hz, J₂=8.5 Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 4.61 (t, J=8.7 Hz,2H), 4.31 (s br, 4H), 3.79-3.82 (m, 2H), 3.42-3.48 (m, 2H), 3.24 (t,J=8.7 Hz, 2H), 1.84-1.90 (m, 2H), 1.52-1.60 (m, 2H).

Example 102: ¹H NMR (400 MHz, D₆-DMSO) δ: 10.09 (s, 1H), 7.91 (s, 1H),7.84 (s, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.42 (d,J=8.1 Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 4.61 (t, J=8.8 Hz, 2H), 4.53-4.58(m, 2H), 4.44-4.49 (m, 2H), 3.62-3.70 (m, 2H), 3.54-3.60 (m, 2H),3.43-3.49 (m, 1H), 3.24 (t, J=8.8 Hz, 2H), 2.36-2.42 (m, 4H).

Example 103: ¹H NMR (400 MHz, D₆-DMSO) δ: 10.09 (s, 1H), 7.93 (d, J=1.4Hz, 1H), 7.84 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H),7.41 (dd, J₁=1.5 Hz, J₂=8.3 Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 5.25(quint, J=6.8 Hz, 1H), 4.75-4.85 (m, 4H), 4.61 (t, J=8.6 Hz, 2H),3.22-3.27 (t, J=8.6 Hz, 2H), 3.21 (s, 3H).

Example 109: ¹H NMR (400 MHz, D₆-DMSO) δ: 10.09 (s, 1H), 7.90 (s, 1H),7.84 (s, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.43 (d,J=8.5 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.09 (d, J=6.5 Hz, 1H), 4.64-4.70(m, 1H), 4.61 (t, J=8.6 Hz, 2H), 4.28-4.34 (m, 2H), 3.87 (dd, J₁=4.4 Hz,J₂=8.6 Hz, 2H), 3.24 (t, J=8.7 Hz, 2H).

Example 116: ¹H NMR (400 MHz, D₆-DMSO) δ: 10.07 (s, 1H), 7.85 (s, 1H),7.83 (s, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.38 (dd,J₁=1.0 Hz, J₂=8.6 Hz, 1H), 6.85 (d, J=8.3 Hz, 1H), 5.25 (d, J=3.9 Hz,1H), 4.61 (t, J=8.8 Hz, 2H), 3.57-3.76 (m, 2H), 3.19-3.30 (m, 3H), 3.08(dd, J₁=8.6 Hz, J₂=12.7 Hz, 1H), 1.75-1.91 (m, 2H), 1.40-1.54 (m, 2H).

Example 118 2,3-Dihydro-benzofuran-5-carboxylic acid(2-azetidin-1-yl-benzooxazol-5-yl)-amide

A solution of 2,3-dihydrobenzo[b]furan-5-carboxylic acid (30.3 mg, 0.185mmol), HBTU (70.1 mg, 0.185 mmol) and DIPEA (95 μL, 0.554 mmol) in DMF(1 mL) was stirred at rt for 30 min before2-azetidin-1-yl-benzooxazol-5-ylamine (35 mg, 0.185 mmol, IntermediateA40) was added. The mixture was stirred at 50° C. for 16 h before it wasseparated by prep. HPLC to give the title compound (59 mg) as acolourless resin; LC-MS: t_(R)=0.72 min; [M+H]⁺=336.09; ¹H NMR (400 MHz,CDCl₃): δ 7.81 (s, 1H), 7.77 (s, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.52 (s,1H), 7.42 (d, J=8.7 Hz, 1H), 7.24 (d, J=8.6 Hz, 1H), 6.86 (d, J=8.3 Hz,1H), 4.69 (t, J=8.8 Hz, 2H), 4.33 (t, J=7.6 Hz, 4H), 3.30 (t, J=8.7 Hz,2H), 2.54 (quint, J=7.5 Hz).

Examples 119 to 195

The following Example compounds were prepared in analogy to Example 118starting from Intermediates A2 to A6, A8, A12, A16, A17, A25, A36, A37,and A40 to A48 and the appropriate benzoic acid derivatives.

Exam- LC-MS ple Name t_(R) [min] [M + H]⁺ 1192,3-Dihydro-benzofuran-5-carboxylic 0.67 324.09 acid(2-ethylamino-benzooxazol-5-yl)- amide 1202,3-Dihydro-benzofuran-5-carboxylic 0.66 413.26 acid[2-(3-pyridin-2-yl-azetidin-1-yl)- benzooxazol-5-yl]-amide 121Benzo[1,3]dioxole-5-carboxylic 0.89 374.02 acid[2-(3,3-difluoro-azetidin-1-yl)- benzooxazol-5-yl]-amide 122Benzo[1,3]dioxole-5-carboxylic 0.72 353.89 acid[2-(3-hydroxy-azetidin-1-yl)- benzooxazol-5-yl]-amide 123Benzo[1,3]dioxole-5-carboxylic 1.01 378.07 acid[2-(1-aza-spiro[3.3]hept-1-yl)- benzooxazol-5-yl]-amide 124Benzo[1,3]dioxole-5-carboxylic 0.79 380.05 acid[2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)- benzooxazol-5-yl]-amide 125Benzo[1,3]dioxole-5-carboxylic 0.83 394.06 acid[2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)- benzooxazol-5-yl]-amide 126Benzo[1,3]dioxole-5-carboxylic 0.85 408.10 acid[2-(7-oxa-1-aza-spiro[3.5]non-1-yl)- benzooxazol-5-yl]-amide 127Benzo[1,3]dioxole-5-carboxylic 0.89 352.04 acid(2-pyrrolidin-1-yl-benzooxazol-5-yl)- amide 128Benzo[1,3]dioxole-5-carboxylic 0.76 394.26 acid[2-(2-oxa-5-aza-spiro[3.4]oct-5-yl)- benzooxazol-5-yl]-amide 129Benzo[1,3]dioxole-5-carboxylic 0.97 266.04 acid(2-piperidin-1-yl-benzooxazol-5-yl)- amide 130Benzo[1,3]dioxole-5-carboxylic 0.94 401.83 acid[2-(3,3-difluoro-piperidin-1-yl)- benzooxazol-5-yl]-amide 131Benzo[1,3]dioxole-5-carboxylic 0.88 396.08 acid[2-(4-methoxy-piperidin-1-yl)- benzooxazol-5-yl]-amide 132Benzo[1,3]dioxole-5-carboxylic 0.83 408.10 acid[2-(2-oxa-7-aza-spiro[3.5]non-7-yl)- benzooxazol-5-yl]-amide 133Benzo[1,3]dioxole-5-carboxylic 0.84 408.10 acid[2-(2-oxa-6-aza-spiro[3.5]non-6-yl)- benzooxazol-5-yl]-amide 134Benzo[1,3]dioxole-5-carboxylic 0.95 401.84 acid[2-(4,4-difluoro-piperidin-1-yl)- benzooxazol-5-yl]amide 135Benzo[1,3]dioxole-5-carboxylic 0.75 382.08 acid[2-(4-hydroxy-piperidin-1-yl)- benzooxazol-5-yl]amide 136Benzo[1,3]dioxole-5-carboxylic 0.81 368.03 acid (2-morpholin-4-ylbenzooxazol-5-yl)- amide 137 Benzo[1,3]dioxole-5-carboxylic 0.79 381.10acid [2-(4-methyl-piperazin-1-yl)- benzooxazol-5-yl]-amide 138Benzo[1,3]dioxole-5-carboxylic 0.84 394.07 acid[2-(cyclopropyl-oxetan-3-yl-amino)- benzooxazol-5-yl]-amide 139Benzo[1,3]dioxole-5-carboxylic 0.95 353.90 acid (2-diethylamino-benzooxazol-5-yl]-amide 140 Chroman-6-carboxylic acid 0.78 366.05[2-(3-hydroxy-azetidin-1-yl)- benzooxazol-5-yl]- amide 141Chroman-6-carboxylic acid 0.95 385.84 [2-(3,3-difluoro-azetidin-1-yl)-benzooxazol-5-yl]- amide 142 Chroman-6-carboxylic acid 1.06 390.10[2-(1-aza-spiro[3.3]hept- 1-yl)-benzooxazol-5-yl]- amide 143Chroman-6-carboxylic acid 0.85 392.09 [2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazol- 5-yl]-amide 144 Chroman-6-carboxylic acid 0.89 406.09[2-(6-oxa-1-aza-spiro[3.4]oct- 1-yl)-benzooxazol- 5-yl]-amide 145Chroman-6-carboxylic acid 0.91 420.13 [2-(7-oxa-1-aza-spiro[3.5]non-1-yl)-benzooxazol- 5-yl]-amide 146 Chroman-6-carboxylic acid 0.94 364.06(2-pyrrolidin-1-yl- benzooxazol-5-yl)-amide 147 Chroman-6-carboxylicacid 0.80 406.28 [2-(2-oxa-5-aza-spiro[3.4]oct- 5-yl)-benzooxazol-5-yl]-amide 148 Chroman-6-carboxylic acid 1.03 378.09(2-piperidin-1-yl-benzooxazol- 5-yl]-amide 149 Chroman-6-carboxylic acid1.01 414.11 [2-(4,4-difluoro-piperidin- 1-yl)-benzooxazol-5-yl]- amide150 Chroman-6-carboxylic acid 1.00 141.09 [2-(3,3-difluoro-piperidin-1-yl)-benzooxazol-5-yl]- amide 151 Chroman-6-carboxylic acid 0.81 394.10[2-(4-hydroxy-piperidin- 1-yl)-benzooxazol-5-yl]- amide 152Chroman-6-carboxylic acid 0.94 408.13 [2-(4-methoxy-piperidin-1-yl)-benzooxazol-5-yl]- amide 153 Chroman-6-carboxylic acid 0.89 420.15[2-(2-oxa-7-aza-spiro[3.5]non- 7-yl)-benzooxazol- 5-yl]-amide 154Chroman-6-carboxylic acid 0.90 420.14 [2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol- 5-yl]-amide 155 Chroman-6-carboxylic acid 0.87 380.09(2-morpholin-4-yl-benzooxazol- 5-yl]-amide 156 Chroman-6-carboxylic acid0.85 393.11 [2-(4-methyl-piperazin-1- yl)-benzooxazol-5-yl]- amide 157Chroman-6-carboxylic acid 1.00 366.12 (2-diethylamino-benzooxazol-5-yl)-amide 158 Chroman-6-carboxylic acid 0.90 406.12[2-(cyclopropyl-oxetan- 3-yl-amino)-benzooxazol- 5-yl]-amide 1592,3-Dihydro-benzo[1,4]dioxine-6- 0.72 368.04 carboxylic acid[2-(3-hydroxy-azetidin-1-yl)- benzooxazol-5-yl]-amide 1602,3-Dihydro-benzo[1,4]dioxine- 0.79 394.07 6-carboxylic acid[2-(6-oxa-1-aza- spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide 1612,3-Dihydro-benzo[1,4]dioxine-6- 1.01 392.08 carboxylic acid[2-(1-aza-spiro[3.3]hept-1- yl)-benzooxazol-5-yl]-amide 1622,3-Dihydro-benzo[1,4]dioxine- 0.83 408.11 6-carboxylic acid[2-(6-oxa-1-aza- spiro[3.4]oct-1-yl)-benzooxazol-5-yl]-amide 1632,3-Dihydro-benzo[1,4]dioxine- 0.86 422.12 6-carboxylic acid[2-(7-oxa-1-aza- spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide 1642,3-Dihydro-benzo[1,4]dioxine- 0.89 366.05 6-carboxylic acid(2-pyrrolidin-1-yl- benzooxazol-5-yl]-amide 1652,3-Dihydro-benzo[1,4]dioxine- 0.76 408.27 6-carboxylic acid[2-(2-oxa-5-aza- spiro[3.4]oct-5-yl)-benzooxazol-5-yl]-amide 1662,3-Dihydro-benzo[1,4]dioxine-6- 0.98 380.09 carboxylic acid(2-piperidin-1-yl- benzooxazol-5-yl]-amide 1672,3-Dihydro-benzo[1,4]dioxine-6- 0.75 396.09 carboxylic acid[2-(4-hydroxy-piperidin-1-yl)- benzooxazol-5-yl]-amide 1682,3-Dihydro-benzo[1,4]dioxine-6- 0.94 416.09 carboxylic acid[2-(3,3-difluoro-piperidin-1- yl)-benzooxazol-5-yl]-amide 1692,3-Dihydro-benzo[1,4]dioxine-6- 0.88 410.11 carboxylic acid[2-(4-methoxy-piperidin-1- yl)-benzooxazol-5-yl]-amide 1702,3-Dihydro-benzo[1,4]dioxine-6- 0.95 416.09 carboxylic acid[2-(4,4-difluoro-piperidin-1- yl)-benzooxazol-5-yl]-amide 1712,3-Dihydro-benzo[1,4]dioxine- 0.85 422.12 6-carboxylic acid[2-(2-oxa-6-aza- spiro[3.5]non-6-yl)-benzooxazol-5-yl]amide 1722,3-Dihydro-benzo[1,4]dioxine- 0.83 422.12 6-carboxylic acid[2-(2-oxa-7-aza- spiro[3.5]non-7-yl)-benzooxazol-5-yl]amide 1732,3-Dihydro-benzo[1,4]dioxine- 0.81 382.09 6-carboxylic acid(2-morpholin-4-yl- benzooxazol-5-yl)-amide 1742,3-Dihydro-benzo[1,4]dioxine-6- 0.79 395.11 carboxylic acid[2-(4-methyl-piperazin-1-yl)- benzooxazol-5-yl]-amide 1752,3-Dihydro-benzo[1,4]dioxine-6- 0.95 368.07 carboxylic acid(2-diethylamino- benzooxazol-5-yl)-amide 1762,3-Dihydro-benzo[1,4]dioxine-6- 0.85 408.10 carboxylic acid[2-(cyclopropyl-oxetan-3-yl amino)-benzooxazol-5-yl]-amide 1774-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine- 0.72 381.08 6-carboxylic acid[2-(3-hydroxy- azetidin-1-yl)-benzooxazol-5-yl]-amide 1784-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine- 0.92 401.03 6-carboxylic acid[2-(3,3-difluoro- azetidin-1-yl)-benzooxazol-5-yl]-amide 1794-Methyl-3,4-dihydro-2H- 0.96 405.12 benzo[1,4]oxazine-6-carboxylic acid[2-(1-aza-spiro[3.3]hept- 1-yl)-benzooxazol-5-yl]-amide 1804-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine- 0.81 407.10 6-carboxylic acid[2-(6-oxa-1- aza-spiro[3.3]hept-1-yl)- benzooxazol-5-yl]-amide 1814-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine- 0.82 421.11 6-carboxylic acid[2-(6-oxa-1- aza-spiro[3.4]oct-1-yl)- benzooxazol-5-yl]-amide 1824-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine- 0.83 435.13 6-carboxylic acid[2-(7-oxa-1- aza-spiro[3.5]non-1-yl)- benzooxazol-5-yl]-amide 1834-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine- 0.79 379.13 6-carboxylic acid(2-pyrrolidin-1- yl-benzooxazol-5-yl)-amide 1844-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine- 0.78 421.26 6-carboxylic acid[2-(2-oxa-5- aza-spiro[3.4]oct-5-yl)- benzooxazol-5-yl]-amide 1854-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine- 0.90 393.12 6-carboxylic acid(2-piperidin-1- yl-benzooxazol-5-yl]-amide 1864-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine- 0.74 409.13 6-carboxylic acid[2-(4-hydroxy- piperidin-1-yl)-benzooxazol-5-yl]-amide 1874-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine- 0.97 429.12 6-carboxylic acid[2-(4,4-difluoro- piperidin-1-yl)-benzooxazol-5-yl]-amide 1884-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine- 0.97 429.14 6-carboxylic acid[2-(3,3-difluoro- piperidin-1-yl)-benzooxazol-5-yl]amide 1894-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine- 0.84 435.14 6-carboxylic acid[2-(2-oxa-6- aza-spiro[3.5]non-6-yl)- benzooxazol-5-yl]-amide 1904-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine- 0.82 435.13 6-carboxylic acid[2-(2-oxa-7- aza-spiro[3.5]non-7-yl)- benzooxazol-5-yl]-amide 1914-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine- 0.86 423.15 6-carboxylic acid[2-(4-methoxy- piperidin-1-yl)-benzooxazol-5-yl]-amide 1924-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine- 0.82 395.09 6-carboxylic acid(2-morphol in-4- yl-benzooxazol-5-yl)-amide 1934-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine- 0.67 408.15 6-carboxylic acid[2-(4-methyl- piperazin-1-yl)-benzooxazol-5-yl]-amide 1944-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine- 0.86 381.12 6-carboxylic acid(2- diethylamino-benzooxazol-5-yl]-amide 1954-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine- 0.85 421.13 6-carboxylic acid[2-(cyclopropyl- oxetan-3-yl-amino)-benzooxazol-5-yl]-amide

Example 124: ¹H NMR (400 MHz, D₆-DMSO): δ 10.07 (s, 1H), 7.80 (s, 1H),7.59 (d, J=8.0 Hz, 1H), 7.53 (d, J=0.7 Hz, 1H), 7.40-7.47 (m, 2H), 7.07(d, J=8.2 Hz, 1H), 6.15 (s, 2H), 5.23 (d, J=7.4 Hz, 2H), 4.67 (d, J=7.4Hz, 2H), 4.02 (t, J=7.2 Hz, 2H), 2.73 (t, J=7.1 Hz, 2H).

Example 133: ¹H NMR (400 MHz, D₆-DMSO): δ 10.04 (s, 1H), 7.73 (s, 1H),7.59 (d, J=8.2 Hz, 1H), 7.53 (s, 1H), 7.37 (s, 2H), 7.07 (d, J=8.1 Hz,1H), 6.15 (s, 2H), 4.32 (s, 4H), 3.84 (s, 2H), 3.54 (t, J=5.1 Hz, 2H),1.86-1.92 (m, 2H), 1.54-1.62 (m, 2H).

Example 144: ¹H NMR (400 MHz, D₃-DMSO): δ 10.00 (s, 1H), 7.70-7.78 (m,3H), 7.34-7.41 (m, 2H), 6.85 (d, J=8.3 Hz, 1H), 4.22 (t, J=4.8 Hz, 2H),4.00-4.13 (m, 4H), 3.79-3.90 (m, 2H), 2.83 (t, J=6.1 Hz, 2H), 2.54-2.65(m, 3H), 2.11-2.20 (m, 1H), 1.93-2.01 (m, 2H).

Example 159: ¹H NMR (400 MHz, DMSO): δ 10.03 (s, 1H), 7.76 (s, 1H),7.49-7.55 (m, 2H), 7.34-7.43 (m, 2H), 7.00 (d, J=8.4 Hz, 1H), 5.91 (d,J=6.7 Hz, 1H), 4.62-4.70 (m, 1H), 4.36-4.43 (m, 2H), 4.29-4.36 (m, 4H),3.94-4.00 (m, 2H).

Example 176: ¹H NMR (400 MHz, D₆-DMSO): δ 10.04 (s, 1H), 7.77 (s, 1H),7.48-7.55 (m, 2H), 7.38-7.44 (m, 2H), 7.00 (d, J=8.3 Hz, 1H), 4.89-5.00(m, 3H), 4.75 (t, J=6.2 Hz, 2H), 4.29-4.37 (m, 4H), 2.93-3.01 (m, 1H),0.88-0.96 (m, 2H), 0.76-0.82 (m, 2H).

Example 186: ¹H NMR (400 MHz, D₆-DMSO): δ 9.94 (s, 1H), 7.72 (s, 1H),7.34 (s, 2H), 7.27 (m, 2H), 6.77-6.81 (m, 1H), 4.87 (d, J=4.0 Hz, 1H),4.29-4.33 (m, 2H), 3.88-3.96 (m, 2H), 3.73-3.80 (m, 2H), 3.27-3.31 (m,2H), 3.19 (d, J=5.2 Hz, 1H), 2.93 (s, 3H), 1.82-1.90 (m, 2H), 1.42-1.52(m, 2H).

Example 196 2-Piperidin-1-yl-benzothiazole-5-carboxylic acid(2,3-dihydro-benzofuran-5-yl)-amide

To a solution of2-chloro-N-(2,3-dihydrobenzofuran-5-yl)benzo[d]thiazole-5-carboxamide(62 mg, 0.174 mmol, Intermediate E2) and piperidine (17.2 μL, 0.174mmol) in THF (1 mL), DIPEA (35 μL, 0.198 mmol) was added. The brownsuspension was stirred at 70° C. for 6 h before another portion ofpiperidine (28 μL, 0.282 mmol) was added. Stirring was continued at 70°C. for 16 h. The mixture was concentrated and the residue was dissolvedin DMF (2 mL) and purified by prep. HPLC to give the title compound (33mg) as a pale yellow resin; LC-MS: t_(R)=0.84 min; [M+H]⁺=380.22; ¹H NMR(500 MHz, CDCl₃): δ 7.96 (d, J=1.5 Hz, 1H), 7.80 (s, 1H), 7.67-7.72 (m,2H), 7.64 (dd, J₁=1.7 Hz, J₂=8.2 Hz, 1H), 7.16 (dd, J₁=2.2 Hz, J₂=8.5Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 4.61 (t, J=8.7 Hz, 2H), 3.63-3.70 (m,4H), 3.26 (t, J=8.7 Hz, 2H), 1.72-1.81 (m, 6H).

Examples 197 to 212

The following Example compounds were prepared in analogy to Example 196starting from Intermediates E2 to E4 and the appropriate anilinederivatives.

Exam- LC-MS ple Name t_(R) [min] [M + H]⁺ 1972-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)- 0.78 394.08benzothiazole-5-carboxylic acid (2,3- dihydro-benzofuran-5-yl)-amide 1982-(4,4-Difluoro-piperidin-1-yl)- 0.89 416.09 benzothiazole-5-carboxylicacid (2,3-dihydro- benzofuran-5-yl)-amide 1992-(1,1-Dioxo-thiomorpholin-4-yl)- 0.76 430.06 benzothiazole-5-carboxylicacid (2,3- dihydro-benzofuran-5-yl)-amide 2002-(4-Methoxy-piperidin-1-yl)- 0.82 410.11 benzothiazole-5-carboxylicacid (2,3-dihydro- benzofuran-5-yl)-amide 2012-(4-Methyl-piperazin-1-yl)- 0.60 395.10 benzothiazole-5-carboxylic acid(2,3-dihydro- benzofuran-5-yl)-amide 2022-(6-Oxa-1-aza-spiro[3.4]oct-1-yl)- 0.76 408.07benzothiazole-5-carboxylic acid (2,3- dihydro-benzofuran-5-yl)-amide 2032-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)- 0.79 410.04benzothiazole-5-carboxylic acid (2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide 2042-(4,4-Difluoro-piperidin-1-yl)- 0.89 432.07 benzothiazole-5-carboxylicacid (2,3-dihydro- benzo[1,4]dioxin-6-yl)-amide 2052-(4-Methoxy-piperidin-1-yl)- 0.83 426.08 benzothiazole-5-carboxylicacid (2,3-dihydro- benzo[1,4]dioxin-6-yl)-amide 2062-(4-Methyl-piperazin-1-yl)- 0.60 411.00 benzothiazole-5-carboxylic acid(2,3-dihydro- benzo[1,4]dioxin-6-yl)-amide 2072-Piperidin-1-yl-benzothiazole- 0.85 396.06 5-carboxylic acid(2,3-dihydro- benzo[1,4]dioxin-6-yl)-amide 2082-(6-Oxa-1-aza-spiro[3.4]oct-1-yl)- 0.77 424.09benzothiazole-5-carboxylic acid (2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide 2092-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)- 0.79 396.00benzothiazole-5-carboxylic acid benzo[1,3]dioxol-5-ylamide 2102-(4-Methoxy-piperidin-1-yl)- 0.83 411.96 benzothiazole-5-carboxylicacid benzo[1,3]dioxol-5-ylamide 2112-(4-Methyl-piperazin-1-yl)-benzothiazole- 0.60 397.06 5-carboxylic acidbenzo[1,3]dioxol- 5-ylamide

Example 197. ¹H NMR (500 MHz, D₆-DMSO): δ 10.08 (s, 1H), 8.21 (d, J=1.6Hz, 1H), 7.95 (d, J=8.2 Hz, 1H), 7.71-7.73 (m, 1H), 7.70 (dd, J₁=1.7 Hz,J₂=8.2 Hz, 1H), 7.46 (dd, J₁=2.2 Hz, J₂=8.5 Hz, 1H), 6.74 (d, J=8.5 Hz,1H), 5.35 (d, J=7.8 Hz, 2H), 4.68 (d, J=7.9 Hz, 2H), 4.53 (t, J=8.7 Hz,2H), 3.97 (t, J=7.1 Hz, 2H), 3.20 (m, J=8.7 Hz, 2H), 2.74 (t, J=7.2 Hz,2H), 1.23-1.30 (m, 2H).

Example 198. ¹H NMR (500 MHz, DMSO): δ 10.07 (s, 1H), 8.10 (d, J=1.6 Hz,1H), 7.93 (d, J=8.3 Hz, 1H), 7.69-7.71 (m, 1H), 7.69 (d, J, =1.7 Hz,J₂=8.4 Hz, 1H), 7.44 (dd, J₁=2.2 Hz, J₂=8.5 Hz, 1H), 6.74 (d, J=8.5 Hz,1H), 4.53 (t, J=8.7 Hz, 2H), 3.74-3.79 (m, 4H), 3.20 (t, J=8.7 Hz, 2H),2.12-2.21 (m, 4H).

Example 207. ¹H NMR (400 MHz, D₆-DMSO): δ 10.05 (s, 1H), 8.04 (d, J=1.5Hz, 1H), 7.88 (d, J=8.2 Hz, 1H), 7.62 (dd, J₁=1.6 Hz, J₂=8.2 Hz, 1H),7.43 (d, J=2.4 Hz, 1H), 7.25 (dd, J₁=2.4 Hz, J₂=8.8 Hz, 1H), 6.82 (d,J=8.8 Hz, 1H), 4.15-4.32 (m, 4H), 3.56-3.65 (m, 4H), 1.57-1.73 (m, 6H).

Example 211. ¹H NMR (500 MHz, D₆-DMSO): δ 10.13 (s, 1H), 8.06 (d, J=1.6Hz, 1H), 7.91 (d, J=8.2 Hz, 1H), 7.65 (dd, J₁=1.7 Hz, J₂=8.2 Hz, 1H),7.48 (d, J=2.0 Hz, 1H), 7.24 (dd, J₁=2.1 Hz, J₂=8.4 Hz, 1H), 6.90 (d,J=8.4 Hz, 1H), 6.01 (s, 2H), 3.60 (m, 4H), 2.44-2.48 (m, 4H), 2.25 (s,3H).

Biological Assays

The nucleotide sequence and the amino acid sequence for the human NOX4(Entrez Gene ID 50507) is known in the art and are published. Thepotency and efficacy of the compounds of Formula (I) are assessed fortheir potential to inhibit the formation of ROS in a cellular assay.

Plasmid Production

The full-length human NOX4 (NM_016931.3) transcript was cloned into thepDONR™221 vector (Life Technologies™) in order to generate, bysite-specific integration according to the recommendation of themanufacturer (Life Technologies™), a recombinant pJTI™ R4 DEST CMV-TOvector containing the NOX4 coding information controlled by tetracycline(tet) responsive tet-on cytomegalovirus promoter (hNOX4 pDEST).

Cell Culture and Transfection

Modified human embryonic kidney cells overexpressing a tet receptor(Jump-In™ T-REx™ HEK293; Life Technologies™) were transfected with theNOX4- containing tet-on vector (hNOX4 pDEST) to generate a stablerecombinant cell pool (hNOX4 T-REx-293). hNOX4 T-REx-293 cells werecultured in DMEM containing 4.5 g/L glucose supplemented with 10% fetalcalf serum, penicillin (100 U/mL), streptomycin (100 μg/mL), geneticin(1 mg/mL), and blasticidin (5 μg/mL) at 37° C. in air with 5% CO2. HumanNox4 expression was induced with tet (1 μg/mL) for 24 h andextracellular H₂O₂ was quantified using the Amplex Red reagent (LifeTechnologies™).

Amplex Red Activity Assay

Inhibitory activities on NOX4 have been measured for each examplecompound using the following procedure:

Compounds were prepared as 10 mM stock solution in DMSO vehicle, thendiluted in 384-well plates using DMSO followed by a transfer of thedilutions into the assay plate. As a control, diphenylene iodonium wasincluded at a final concentration of 10 μM. Compounds were tested at 10concentrations in the range from 50 μM highest to 100 nM lowest.

Cellular H₂O₂ formation was measured using the Amplex Red reagent. Cellswere washed with 1×PBS, trypsinized with 1× Trypsin-EDTA, collected bycentrifugation and resuspended in 1×PBS. Cells were seeded into 384-wellclear bottom plates at a density of 20 000 cells per well in presence orabsence of compounds. The assay was started by the addition of AmplexRed and horseradish peroxidase at final concentrations of 25 μM and 0.1U/mL, respectively. All wells contained 1.25% of DMSO. The plates werekept at 25° C. for 60 min. The amount of produced resorufin was detectedwith the Synergy™ Mx microplate reader (BioTek) with excitation andemission wavelengths set to 550 nm and 600 nm, respectively.Fluorescence was measured for each well and the fluorescence at 600 nmwavelength was compared to the fluorescence of the vehicle in place ofcompound. Inhibitory activities of example compounds were determined bycalculating the IC₅₀ value (the concentration of compound needed toinhibit 50% of the enzyme activity). The calculated IC₅₀ values mayfluctuate depending on the daily cellular assay performance.Fluctuations of this kind are known to those skilled in the art. In thecase where IC₅₀ values have been determined several times for the samecompound, the geometric mean is given. IC₅₀ values of exemplifiedcompounds are displayed in the Table below.

Amplex Red Counter Screen Assay

In order to identify compounds that interfere with the activity assayeither by inhibiting the activity of horseradish peroxidase or bydirectly interacting with the formed H₂O₂ a counter screen assay wasestablished. This control assay is almost identical to the describedAmplex Red activity assay with the only difference that the H₂O₂—generating cells are replaced by 1562.5 nM H₂O₂ in 1×PBS.

TABLE 1 Compound IC₅₀ IC₅₀ of Amplex Control Example [nM] [μM 1 344 >502 639 >50 3 899 >50 4 967 >50 5 627 >50 6 559 >50 7 358 >50 8 1890 >50 9573 >50 10 711 >50 11 358 >50 12 688 >50 13 5360 >50 14 1700 >50 15405 >50 16 389 >50 17 2300 >50 18 568 >50 19 2890 >50 20 1400 >50 211610 >50 22 505 >50 23 1470 >50 24 352 >50 25 804 >50 26 1490 >50 27729 >50 28 695 >50 29 541 >50 30 1230 >50 31 2170 >50 32 2410 >50 332140 >50 34 1220 >50 35 379 >50 36 404 >50 37 841 >50 38 1750 >50 39444 >50 40 812 >50 41 2520 >50 42 566 >50 43 541 >50 44 1140 >50 45573 >50 46 570 >50 47 657 >50 48 448 >50 49 1230 >50 50 451 >50 514570 >50 52 899 >50 53 913 >50 54 2910 >50 55 400 >50 56 906 >50 57681 >50 58 1330 >50 59 731 >50 60 1670 >50 61 5240 >50 62 702 >50 63359 >50 64 2130 >50 65 851 >50 66 4170 >50 67 3080 >50 68 1790 >50 691930 >50 70 889 >50 71 336 >50 72 524 >50 73 4100 >50 74 1080 >50 75421 >50 76 414 >50 77 548 >50 78 417 >50 79 585 >50 80 312 >50 812450 >50 82 2350 >50 83 3540 >50 84 1320 >50 85 1650 >50 86 2680 >50 874100 >50 88 3660 >50 89 1920 >50 90 361 >50 91 4331 >50 92 2460 >50 9310300 >50 94 3290 >50 95 2140 >50 96 2670 >50 97 6303 >50 98 2530 >50 993080 >50 100 3390 >50 101 2370 >50 102 9170 >50 103 3210 >50 1046870 >50 105 14800 >50 106 9390 >50 107 9510 >50 108 2540 >50 1091780 >50 110 2030 >50 111 1090 >50 112 2270 >50 113 3250 >50 1142940 >50 115 3410 >50 116 2170 >50 117 3760 >50 118 504 >50 119 990 >50120 2340 >50 121 9530 >50 122 2110 >50 123 434 >50 124 414 >50 125772 >50 126 757 >50 127 1250 >50 128 1740 >50 129 857 >50 130 991 >50131 1050 >50 132 1080 >50 133 614 >50 134 870 >50 135 1090 >50 1361280 >50 137 1640 >50 138 1480 >50 139 1090 >50 140 2520 >50 14110600 >50 142 891 >50 143 681 >50 144 1540 >50 145 1400 >50 146 3180 >50147 379 >50 148 1880 >50 149 1430 >50 150 2200 >50 151 1410 >50 1521350 >50 153 1300 >50 154 1130 >50 155 756 >50 156 1790 >50 157 2030 >50158 2860 >50 159 1480 >50 160 541 >50 161 665 >50 162 954 >50 1631140 >50 164 1280 >50 165 764 >50 166 1500 >50 167 1220 >50 168 1140 >50169 793 >50 170 899 >50 171 792 >50 172 8850 >50 173 1420 >50 1741390 >50 175 1350 >50 176 2970 >50 177 6870 >50 178 21800 >50 1791740 >50 180 1770 >50 181 2440 >50 182 3390 >50 183 8700 >50 1841890 >50 185 3860 >50 186 3450 >50 187 3390 >50 188 3640 >50 1892190 >50 190 3580 >50 191 4380 >50 192 4320 >50 193 4040 >50 1943580 >50 195 4440 >50 196 2560 >50 197 728 >50 198 45200 >50 19923900 >50 200 2750 >50 201 2870 >50 202 729 >50 203 1840 >50 20425500 >50 205 26800 >50 206 21200 >50 207 12800 >50 208 2710 >50 2091500 >50 210 6900 >50 211 8900 >50

1-17. (canceled)
 18. A method to prevent or treat a disease or disorderselected from a fibrotic disease; pulmonary hypertension; hypertension;asthma; acute respiratory distress syndrome; myocardial infarction;acute heart failure; cardiac and skeletal myopathy including Barthsyndrome; stroke; traumatic brain injury; neuropathic pain; ataxiatelangiectasia; ocular diseases; and cancer; comprising administering toa patient in need thereof, a pharmaceutically effective amount of acompound of the Formula (I),

wherein ring (A) represents a non-aromatic 5- to 7-membered heterocyclicring which is fused to the phenyl group; wherein said 5- to 7-memberedheterocyclic ring contains one oxygen ring atom and optionally onefurther ring heteroatom independently selected from oxygen or nitrogen;wherein said 5- to 7-membered heterocyclic ring independently isunsubstituted, or mono-, or di-substituted, wherein the substituents areindependently selected from: one oxo substituent attached to a ringcarbon atom in alpha position to a ring oxygen and/or a ring nitrogenatom; and/or one C1-3-alkyl attached to a ring nitrogen atom having afree valency; or two fluoro substituents attached to the same ringcarbon atom; L represents —NH—CO—* or —CO—NH—*, wherein the asterisks(*) indicate the bond that is linked to the benzoxazole moiety; Xrepresents O; and Y represents —NR¹R² wherein R¹ represents C₁₋₄-alkyl;C₂₋₄-alkyl which is mono-substituted with di-(C₁₋₃-alkyl)amino, hydroxyor C₁₋₃-alkoxy; C₃₋₅-cycloalkyl-L¹-, wherein L1 represents a direct bondor C₁₋₃-alkylene; and wherein the C₃₋₅-cycloalkyl optionally containsone oxygen ring atom, and wherein said C₃₋₅-cycloalkyl is unsubstituted,or mono-substituted with methyl or fluoro; or a piperidin-3-yl,piperidin-4-yl or pyrrolidin-3-yl group, which groups are substituted onthe ring nitrogen atom with C₃₋₅-cycloalkyl, wherein saidC₃₋₅-cycloalkyl optionally contains one oxygen ring atom; and R²represents hydrogen, C1-3-alkyl, or C3-5-cycloalkyl; or Y represents asaturated 4- to 7-membered monocyclic heterocyclyl selected from:morpholin-4-yl; 2-oxo-pyrrolidin-1-yl; 1,1-dioxidothiomorpholin-4-yl; orpiperazin-1-yl optionally mono-substituted in position 4 withoxetan-3-yl or C₁₋₃-alkyl; or azetidin-1-yl, pyrrolidin-1-yl, orpiperidin-1-yl; wherein said azetidin-1-yl, pyrrolidin-1-yl, orpiperidin-1-yl independently is unsubstituted, or substituted with: twofluoro substituents attached to the same ring carbon atom; or onesubstituent selected from unsubstituted phenyl, or unsubstituted 5- or6-membered heteroaryl; or one substituent selected from hydroxy;C1-3-alkoxy; —CO—C₁₋₄-alkoxy; di-(C₁₋₃-alkyl)amino; and C₁₋₃-alkyl whichis mono-substituted with di-(C₁₋₃-alkyl)amino, hydroxy, or C₁₋₃-alkoxy;or two substituents, wherein one of said substituents is C₁₋₄-alkyl, andthe other is independently selected from hydroxy, ordi-(C₁₋₃-alkyl)amino; or one substituent selected from morpholin-4-yl;1,1-dioxidothiomorpholin-4-yl; or piperazin-1-yl which is optionallymono-substituted in position 4 with C₁₋₃-alkyl; one substituent selectedfrom azetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl; wherein saidgroups independently are unsubstituted, or mono-substituted withhydroxy, or di-substituted with methyl and hydroxy; or Y representssaturated 7- to 11-membered fused, bridged, or spiro-bicyclicheterocyclyl containing at least one nitrogen atom, wherein saidnitrogen atom is bound to the benzoxazole moiety, and wherein saidheterocyclyl optionally contains one further ring heteroatomindependently selected from oxygen, nitrogen and sulfur; wherein saidheterocyclyl is unsubstituted, or substituted with: two oxo substituentsat a ring sulfur ring atom; or one C₁₋₃-alkyl substituent attached to aring nitrogen atom having a free valency; in free or pharmaceuticallyacceptable salt form.
 19. The method according to claim 18, wherein saidfibrotic disease is pulmonary fibrosis; scleroderma; pancreaticfibrosis; liver fibrosis; chronic kidney disease; or cardiomyopathy. 20.The method according to claim 18, wherein in said compound of theFormula (I) the fragment

represents a group selected from:

wherein R^(a) represents hydrogen, or C₁₋₃-alkyl; or a pharmaceuticallyacceptable salt thereof.
 21. The method according to claim 18, whereinin said compound of the Formula (I) the fragment

represents

or a pharmaceutically acceptable salt thereof.
 22. The method accordingto claim 18, wherein in said compound of the Formula (I) L represents—CO—NH—*, wherein the asterisk (*) indicates the bond that is linked tothe benzoxazole moiety; or a pharmaceutically acceptable salt thereof.23. The method according to claim 18, wherein in said compound of theFormula (I) Y represents a group —NR¹R², wherein R¹ represents)C₂₋₄-alkyl which is mono-substituted with di-(C₁₋₃-alkyl)amino;C₃₋₅-cycloalkyl-L¹-, wherein L1 represents a direct bond orC₁₋₃-alkylene; and wherein the C₃₋₅-cycloalkyl optionally contains oneoxygen ring atom, and wherein said C₃₋₅-cycloalkyl is unsubstituted, ormono-substituted with methyl or fluoro; or1-(oxetan-3-yl)-piperidin-4-yl; and R² represents hydrogen, C₁₋₃-alkyl,or C₃₋₅-cycloalkyl; or Y represents a group

wherein r and q both represent the integer 2; and Z represents O, SO₂,or NR^(Y1), wherein R^(Y1) represents oxetan-3-yl or C₁₋₃-alkyl; or rrepresents the integer 0, 1, 2, or 3; q represents the integer 1, 2, 3,or 4; and the sum of r and q is 2, 3, or 4; Z represents CH₂, CHR^(Y2),or CR^(Y3)R^(Y3)R^(Y4); wherein R^(Y2) represents unsubstituted phenyl,or unsubstituted 5- or 6-membered heteroaryl; hydroxy; C₁₋₃-alkoxy;—CO—C₁₋₄-alkoxy; di-(C₁₋₃-alkyl)amino; or C₁₋₃-alkyl which ismono-substituted with di-(C₁₋₃-alkyl)amino, hydroxy, or C₁₋₃-alkoxy;morpholin-4-yl; 1,1-dioxidothiomorpholin-4-yl; or piperazin-1-yl whichis optionally mono-substituted in position 4 with C₁₋₃-alkyl; orazetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl; wherein said groupsindependently are unsubstituted, or mono-substituted with hydroxy, ordi-substituted with methyl and hydroxy; and —R^(Y3) representsC₁₋₄-alkyl; and R^(Y4) independently represents hydroxy, ordi-(C₁₋₃-alkyl)amino; or R^(Y3) and R^(Y4) both represent fluoro; orR^(Y3) and R^(Y4) together with the carbon atom to which they areattached to form a 4- to 6-membered saturated carbocyclic ring; or a 4-to 6-membered saturated heterocyclic ring, wherein said heterocyclicring contains one ring heteroatom independently selected from oxygen,nitrogen and sulfur; and wherein said heterocyclic ring isunsubstituted, or substituted with: two oxo substituents at a ringsulfur ring atom; or one C₁₋₃-alkyl substituent attached to a ringnitrogen atom having a free valency; or a pharmaceutically acceptablesalt thereof.
 24. The method according to claim 18, wherein in saidcompound of the Formula (I) Y represents N—(C₁₋₃-alkyl)amino,N,N-di-(C₁₋₃-alkyl)-amino,N-[2-(di-C₁₋₃-alkyl)amino)-ethyl]-N—(C₁₋₃-alkyl)-amino,N—(C₁₋₄-alkyl)-N-(oxetan-3-yl)-amino,N—(C₃₋₅-cycloalkyl)-N-(oxetan-3-yl)-amino,N—(C₁₋₄-alkyl)-N-(oxetan-3-yl-methyl)-amino,N-(3-methyl-oxetan-3-yl)-N-methylamino,N-(3-fluoro-oxetan-3-yl-methyl)-N-methylamino, orN-methyl-((N-(oxetan-3-yl)-piperidin)-4-yl)-amino; or Y represents asaturated 4- to 7-membered monocyclic heterocyclyl selected from:morpholin-4-yl; 2-oxo-pyrrolidin-1-yl; 1,1-dioxidothiomorpholin-4-yl; orpiperazin-1-yl optionally mono-substituted in position 4 withoxetan-3-yl or C₁₋₃-alkyl; or azetidin-1-yl which is unsubstituted, orsubstituted with: two fluoro substituents attached to the same ringcarbon atom; or one phenyl or pyridinyl substituent, wherein said phenylor pyridinyl is unsubstituted; or one substituent selected from hydroxy;C₁₋₃-alkoxy; —CO—C₁₋₄-alkoxy; di-(C₁₋₃-alkyl)amino; and C₁₋₃-alkyl whichis mono-substituted with di-(C₁₋₃-alkyl)amino, hydroxy, or C₁₋₃-alkoxy;or two substituents, wherein one of said substituents is C₁₋₄-alkyl, andthe other is independently selected from hydroxy, ordi-(C₁₋₃-alkyl)amino; or one substituent selected from morpholin-4-yl;1,1-dioxidothiomorpholin-4-yl; one substituent selected fromazetidin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl; wherein said groupsindependently are unsubstituted, or mono-substituted with hydroxy, ordi-substituted with methyl and hydroxy; or pyrrolidin-1-yl, orpiperidin-1-yl; wherein said pyrrolidin-1-yl, or piperidin-1-ylindependently is unsubstituted, or substituted with: two fluorosubstituents attached to the same ring carbon atom; or one substituentselected from hydroxy; C₁₋₃-alkoxy; or di-(C₁₋₃-alkyl)amino; or Yrepresents saturated 7- to 11-membered spiro-bicyclic heterocyclylcontaining at least one nitrogen atom, wherein said nitrogen atom isbound to the benzoxazole moiety, and wherein said heterocyclyloptionally contains one further ring heteroatom independently selectedfrom oxygen, nitrogen and sulfur; wherein said heterocyclyl isunsubstituted, or substituted with: two oxo substituents at a ringsulfur ring atom; or one C₁₋₃-alkyl substituent attached to a ringnitrogen atom having a free valency; or a pharmaceutically acceptablesalt thereof.
 25. The method according to claim 18, wherein in saidcompound of the Formula (I) Y represents a group independently selectedfrom the following groups A), B), C), or D):

or a pharmaceutically acceptable salt thereof.
 26. The method accordingto claim 18, wherein in said compound of the Formula (I) Y represents agroup independently selected from the following groups A) or B):

or a pharmaceutically acceptable salt thereof.
 27. The method accordingto claim 18, wherein said compound of the Formula (I) is selected fromthe group consisting of: 2,3-Dihydro-benzofuran-5-carboxylic acid[2-(1,1-dioxo-1l6-thiomorpholin-4-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid(2-piperidin-1-yl-benzooxazol-5-yl)-amide;2,3-Dihydro-benzofuran-5-carboxylic acid(2-pyrrolidin-1-yl-benzooxazol-5-yl)-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(4-methyl-piperazin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid(2-morpholin-4-yl-benzooxazol-5-yl)-amide;2,3-Dihydro-benzofuran-5-carboxylic acid(2-diethylamino-benzooxazol-5-yl)-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(4,4-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(3,3-difluoro-azetidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(3,3-difluoro-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(3-methoxy-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(4-methoxy-piperidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(3-hydroxy-3-methyl-azetidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(4-dimethylamino-piperidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(3,3-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(3-morpholin-4-yl-azetidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid{2-[methyl-(3-methyl-oxetan-3-yl)-amino]-benzooxazol-5-yl}-amide;2,3-Dihydro-benzofuran-5-carboxylic acid{2-[3-(1,1-dioxo-1l6-thiomorpholin-4-yl)-azetidin-1-yl]-benzooxazol-5-yl}-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(3-hydroxy-3-methyl-[1,3]biazetidinyl-1′-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(1-oxa-6-aza-spiro[3.3]hept-6-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(2-oxa-6-aza-spiro[3.4]oct-6-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(6-oxa-2-aza-spiro[3.5]non-2-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(1-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(2-oxa-5-aza-spiro[3.5]non-5-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(1-oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(1-oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(1-oxa-8-aza-spiro[4.5]dec-8-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(7-oxa-2-aza-spiro[3.5]non-2-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(5-oxa-2-aza-spiro[3.4]oct-2-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid{2-[3-(4-hydroxy-piperidin-1-yl)-azetidin-1-yl]-benzooxazol-5-yl}-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(6-methyl-2,6-diaza-spiro[3.5]non-2-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(5-oxa-2-aza-spiro[3.5]non-2-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid [2-(1-aza-spiro[30.3]hept-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(7-oxa-1-aza-spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide;1-{5-[(2,3-Dihydro-benzofuran-5-carbonyl)-amino]-benzooxazol-2-yl}-azetidine-3-carboxylicacid tert-butyl ester; 2,3-Dihydro-benzofuran-5-carboxylic acid[2-(2-oxo-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid[2-(1,1-dioxo-thiomorpholin-4-yl)-benzooxazol-5-yl]-amide;Chroman-6-carboxylic acid[2-(1,1-dioxo-thiomorpholin-4-yl)-benzooxazol-5-yl]-amide;4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid[2-(1,1-dioxo-thiomorpholin-4-yl)-benzooxazol-5-yl]-amide;(R)—N-(2-(3-hydroxypiperidin-1-yl)benzo[d]oxazol-5-yl)-2,3-dihydrobenzofuran-5-carboxamide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-((S)-3-hydroxy-piperidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(3-isopropoxy-azetidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-((R)-3-hydroxy-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-((S)-3-hydroxy-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(3-hydroxy-azetidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(4-hydroxy-piperidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(3-phenyl-azetidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(2-ethoxymethyl-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid{2-[(3-fluoro-oxetan-3-ylmethyl)-methyl-amino]-benzooxazol-5-yl}-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(4-oxetan-3-yl-piperazin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid{2-[methyl-(1-oxetan-3-yl-piperidin-4-yl)-amino]-benzooxazol-5-yl}-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(methyl-oxetan-3-ylmethyl-amino)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(methyl-oxetan-3-yl-amino)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(2-methoxymethyl-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(3-methoxy-piperidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(3-dimethylaminomethyl-pyrrolidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(2-phenyl-azetidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(cyclopropyl-oxetan-3-yl-amino)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(3-pyrrolidin-1-yl-azetidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid{2-[3-(1-hydroxy-1-methyl-ethyl)-azetidin-1-yl]-benzooxazol-5-yl}-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(3-dimethylaminomethyl-azetidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(7-methyl-1,7-diaza-spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(7-methyl-2,7-diaza-spiro[3.5]non-2-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(3-dimethylamino-azetidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(2,2-dioxo-2l6-thia-6-aza-spiro[3.3]hept-6-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(1,1-dioxo-1l6-thia-6-aza-spiro[3.3]hept-6-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(3-dimethylamino-3-methyl-azetidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(6-oxa-2-aza-spiro[3.4]oct-2-yl)-benzooxazol-5-yl]-amide;2-(4-Methyl-piperazin-1-yl)-benzooxazole-5-carboxylic acid(2,3-dihydro-benzofuran-5-yl)-amide;2-Piperidin-1-yl-benzooxazole-5-carboxylic acid(2,3-dihydro-benzofuran-5-yl)-amide;2-Morpholin-4-yl-benzooxazole-5-carboxylic acid(2,3-dihydro-benzofuran-5-yl)-amide;2-Diethylamino-benzooxazole-5-carboxylic acid(2,3-dihydro-benzofuran-5-yl)-amide;2-Pyrrolidin-1-yl-benzooxazole-5-carboxylic acid(2,3-dihydro-benzofuran-5-yl)-amide;2-(6-Oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazole-5-carboxylic acid(2,3-dihydro-benzofuran-5-yl)-amide; 2,3-Dihydro-benzofuran-5-carboxylicacid (2-azetidin-1-yl-benzooxazol-5-yl)-amide;2,3-Dihydro-benzofuran-5-carboxylic acid(2-ethylamino-benzooxazol-5-yl)-amide;2,3-Dihydro-benzofuran-5-carboxylic acid[2-(3-pyridin-2-yl-azetidin-1-yl)-benzooxazol-5-yl]-amide;Benzo[1,3]dioxole-5-carboxylic acid[2-(3-hydroxy-azetidin-1-yl)-benzooxazol-5-yl]-amide;Benzo[1,3]dioxole-5-carboxylic acid[2-(1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide;Benzo[1,3]dioxole-5-carboxylic acid[2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide;Benzo[1,3]dioxole-5-carboxylic acid[2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)-benzooxazol-5-yl]-amide;Benzo[1,3]dioxole-5-carboxylic acid[2-(7-oxa-1-aza-spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide;Benzo[1,3]dioxole-5-carboxylic acid(2-pyrrolidin-1-yl-benzooxazol-5-yl)-amide;Benzo[1,3]dioxole-5-carboxylic acid[2-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-benzooxazol-5-yl]-amide;Benzo[1,3]dioxole-5-carboxylic acid(2-piperidin-1-yl-benzooxazol-5-yl)-amide;Benzo[1,3]dioxole-5-carboxylic acid[2-(3,3-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide;Benzo[1,3]dioxole-5-carboxylic acid[2-(4-methoxy-piperidin-1-yl)-benzooxazol-5-yl]-amide;Benzo[1,3]dioxole-5-carboxylic acid[2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol-5-yl]-amide;Benzo[1,3]dioxole-5-carboxylic acid[2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol-5-yl]-amide;Benzo[1,3]dioxole-5-carboxylic acid[2-(4,4-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide;Benzo[1,3]dioxole-5-carboxylic acid[2-(4-hydroxy-piperidin-1-yl)-benzooxazol-5-yl]-amide;Benzo[1,3]dioxole-5-carboxylic acid(2-morpholin-4-yl-benzooxazol-5-yl)-amide;Benzo[1,3]dioxole-5-carboxylic acid[2-(4-methyl-piperazin-1-yl)-benzooxazol-5-yl]-amide;Benzo[1,3]dioxole-5-carboxylic acid[2-(cyclopropyl-oxetan-3-yl-amino)-benzooxazol-5-yl]-amide;Benzo[1,3]dioxole-5-carboxylic acid(2-diethylamino-benzooxazol-5-yl)-amide; Chroman-6-carboxylic acid[2-(3-hydroxy-azetidin-1-yl)-benzooxazol-5-yl]-amide;Chroman-6-carboxylic acid[2-(1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide;Chroman-6-carboxylic acid[2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide;Chroman-6-carboxylic acid[2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)-benzooxazol-5-yl]-amide;Chroman-6-carboxylic acid[2-(7-oxa-1-aza-spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide;Chroman-6-carboxylic acid (2-pyrrolidin-1-yl-benzooxazol-5-yl)-amide;Chroman-6-carboxylic acid[2-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-benzooxazol-5-yl]-amide;Chroman-6-carboxylic acid (2-piperidin-1-yl-benzooxazol-5-yl)-amide;Chroman-6-carboxylic acid[2-(4,4-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide;Chroman-6-carboxylic acid[2-(3,3-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide;Chroman-6-carboxylic acid[2-(4-hydroxy-piperidin-1-yl)-benzooxazol-5-yl]-amide;Chroman-6-carboxylic acid[2-(4-methoxy-piperidin-1-yl)-benzooxazol-5-yl]-amide;Chroman-6-carboxylic acid[2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol-5-yl]-amide;Chroman-6-carboxylic acid[2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol-5-yl]-amide;Chroman-6-carboxylic acid (2-morpholin-4-yl-benzooxazol-5-yl)-amide;Chroman-6-carboxylic acid[2-(4-methyl-piperazin-1-yl)-benzooxazol-5-yl]-amide;Chroman-6-carboxylic acid (2-diethylamino-benzooxazol-5-yl)-amide;Chroman-6-carboxylic acid[2-(cyclopropyl-oxetan-3-yl-amino)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid[2-(3-hydroxy-azetidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid[2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid[2-(1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid[2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid[2-(7-oxa-1-aza-spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid(2-pyrrolidin-1-yl-benzooxazol-5-yl)-amide;2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid[2-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid(2-piperidin-1-yl-benzooxazol-5-yl)-amide;2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid[2-(4-hydroxy-piperidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid[2-(3,3-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid[2-(4-methoxy-piperidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid[2-(4,4-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid[2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid(2-morpholin-4-yl-benzooxazol-5-yl)-amide;2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid[2-(4-methyl-piperazin-1-yl)-benzooxazol-5-yl]-amide;2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid(2-diethylamino-benzooxazol-5-yl)-amide;2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid[2-(cyclopropyl-oxetan-3-yl-amino)-benzooxazol-5-yl]-amide;4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid[2-(1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide;4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid[2-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-benzooxazol-5-yl]-amide;4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid[2-(6-oxa-1-aza-spiro[3.4]oct-1-yl)-benzooxazol-5-yl]-amide;4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid[2-(7-oxa-1-aza-spiro[3.5]non-1-yl)-benzooxazol-5-yl]-amide;4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid[2-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-benzooxazol-5-yl]-amide;4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid(2-piperidin-1-yl-benzooxazol-5-yl)-amide;4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid[2-(4-hydroxy-piperidin-1-yl)-benzooxazol-5-yl]-amide;4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid[2-(4,4-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide;4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid[2-(3,3-difluoro-piperidin-1-yl)-benzooxazol-5-yl]-amide;4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid[2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-benzooxazol-5-yl]-amide;4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid[2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-benzooxazol-5-yl]-amide;4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid[2-(4-methoxy-piperidin-1-yl)-benzooxazol-5-yl]-amide;4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid(2-morpholin-4-yl-benzooxazol-5-yl)-amide;4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid[2-(4-methyl-piperazin-1-yl)-benzooxazol-5-yl]-amide;4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid(2-diethylamino-benzooxazol-5-yl)-amide;4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid[2-(cyclopropyl-oxetan-3-yl-amino)-benzooxazol-5-yl]-amide; or apharmaceutically acceptable salt thereof.